Medicine › Physiology

Nitric Oxide and Endothelin Effects

Works Count: 98308

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This cluster of papers explores the role of nitric oxide in health and disease, particularly focusing on its involvement in endothelial dysfunction, oxidative stress, cardiovascular diseases, and the regulation of vascular function. It also delves into the impact of nitric oxide on inflammation, atherosclerosis, and mitochondrial biogenesis.

Keywords

Nitric Oxide; Endothelial Dysfunction; Oxidative Stress; Cardiovascular Diseases; Reactive Oxygen Species; NAD(P)H Oxidase; Atherosclerosis; Vascular Function; Inflammation; Mitochondrial Biogenesis

Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

1998-05-15

Douglas B. Cines , Eleanor S. Pollak , Clayton A. Buck +7 more

Peroxynitrite oxidation of sulfhydryls.

1991-03-01

Rafael Radí , Joseph S. Beckman , Ken Bush +1 more

Peroxynitrite anion (ONOO-) is a potent oxidant that mediates oxidation of both nonprotein and protein sulfhydryls. Endothelial cells, macrophages, and neutrophils can generate superoxide as well as nitric oxide, leading … Peroxynitrite anion (ONOO-) is a potent oxidant that mediates oxidation of both nonprotein and protein sulfhydryls. Endothelial cells, macrophages, and neutrophils can generate superoxide as well as nitric oxide, leading to the production of peroxynitrite anion in vivo. Apparent second order rate constants were 5,900 M-1.s-1 and 2,600-2,800 M-1.s-1 for the reaction of peroxynitrite anion with free cysteine and the single thiol of albumin, respectively, at pH 7.4 and 37 °C. These rate constants are 3 orders of magnitude greater than the corresponding rate constants for the reaction of hydrogen peroxide with sulfhydryls at pH 7.4. Unlike hydrogen peroxide, which oxidizes thiolate anion, peroxynitrite anion reacts preferentially with the undissociated form of the thiol group. Peroxynitrite oxidizes cysteine to cystine and the bovine serum albumin thiol group to an arsenite nonreducible product, suggesting oxidation beyond sulfenic acid. Peroxynitrous acid was a less effective thiol-oxidizing agent than its anion, with oxidation presumably mediated by the decomposition products, hydroxyl radical and nitrogen dioxide. The reactive peroxynitrite anion may exert cytotoxic effects in part by oxidizing tissue sulfhydryls.

The nitrate–nitrite–nitric oxide pathway in physiology and therapeutics

2008-01-02

Jon O. Lundberg , Eddie Weitzberg , Mark T. Gladwin

Nitric oxide and the immune response

2001-10-01

Christian Bogdan

Role of transcription factor NF-kappa B/Rel in induction of nitric oxide synthase.

1994-02-01

Q.W. Xie , Yumiko Kashiwabara , Carl Nathan

The promoter of the murine gene encoding inducible nitric oxide synthase (iNOS) contains an NF-KB site beginning 55 base pairs upstream of the TATA box, designated NF-KBd.Reporter constructs containing truncated … The promoter of the murine gene encoding inducible nitric oxide synthase (iNOS) contains an NF-KB site beginning 55 base pairs upstream of the TATA box, designated NF-KBd.Reporter constructs containing truncated promoter regions, when transfected into macrophages, revealed that NF-KBd is necessary to confer inducibility by bacterial lipopolysaccharide (LPS).Oligonucleotide probes containing NF-KBd plus the downstream 9 or 47 base pairs bound proteins that rapidly appeared in the nuclei of LPS-treated macrophages.The nuclear proteins bound to both probes in an NF-KBd-dependent manner, but binding was resistant to cycloheximide only for the shorter probe.The proteins binding both probes reacted with antibodies against p50 and c-re1 but not Rem; those binding the shorter probe also reacted with anti-RelA ( ~6 5 ) .m o l i d i n e dithiocarbamate, which acts as a specific inhibitor of NF-KB, blocked both the activation of the NF-KBd-binding proteins and the production of NO in LPS-treated macrophages.Thus, activation of NF-KB/Rel is critical in the induction of iNOS by LPS.However, additional, newly synthesized proteins contribute to the NF-KBd-dependent transcription factor complex on the iNOS promoter in LPS-treated mouse macrophages.Nitric oxide (NO) is reported to participate in the physiology or pathophysiology of every organ system (1).

Activation of nitric oxide synthase in endothelial cells by Akt-dependent phosphorylation

1999-06-01

Stefanie Dimmeler , Ingrid Fleming , Beate Fißlthaler +3 more

Regulation of endothelium-derived nitric oxide production by the protein kinase Akt

1999-06-10

David Fulton , Jean‐Philippe Gratton , Timothy J. McCabe +6 more

Nitric oxide synthases in mammals

1994-03-01

Richard G. Knowles , Salvador Moncada

Research Article| March 01 1994 Nitric oxide synthases in mammals R G Knowles; R G Knowles 1Wellcome Research Laboratories, Langley Court, Beckenham BR3 3BS, U.K. Search for other works by … Research Article| March 01 1994 Nitric oxide synthases in mammals R G Knowles; R G Knowles 1Wellcome Research Laboratories, Langley Court, Beckenham BR3 3BS, U.K. Search for other works by this author on: This Site PubMed Google Scholar S Moncada S Moncada 1Wellcome Research Laboratories, Langley Court, Beckenham BR3 3BS, U.K. Search for other works by this author on: This Site PubMed Google Scholar Author and article information Publisher: Portland Press Ltd Online ISSN: 1470-8728 Print ISSN: 0264-6021 © 1994 The Biochemical Society, London1994 Biochem J (1994) 298 (2): 249–258. https://doi.org/10.1042/bj2980249 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Cite Icon Cite Get Permissions Citation R G Knowles, S Moncada; Nitric oxide synthases in mammals. Biochem J 1 March 1994; 298 (2): 249–258. doi: https://doi.org/10.1042/bj2980249 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search All ContentAll JournalsBiochemical Journal Search Advanced Search This content is only available as a PDF. © 1994 The Biochemical Society, London1994 Article PDF first page preview Close Modal You do not currently have access to this content.

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Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly

1996-11-01

Joseph S. Beckman , Willem H. Koppenol

Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction … Nitric oxide contrasts with most intercellular messengers because it diffuses rapidly and isotropically through most tissues with little reaction but cannot be transported through the vasculature due to rapid destruction by oxyhemoglobin. The rapid diffusion of nitric oxide between cells allows it to locally integrate the responses of blood vessels to turbulence, modulate synaptic plasticity in neurons, and control the oscillatory behavior of neuronal networks. Nitric oxide is not necessarily short lived and is intrinsically no more reactive than oxygen. The reactivity of nitric oxide per se has been greatly overestimated in vitro because no drain is provided to remove nitric oxide. Nitric oxide persists in solution for several minutes in micromolar concentrations before it reacts with oxygen to form much stronger oxidants like nitrogen dioxide. Nitric oxide is removed within seconds in vivo by diffusion over 100 microns through tissues to enter red blood cells and react with oxyhemoglobin. The direct toxicity of nitric oxide is modest but is greatly enhanced by reacting with superoxide to form peroxynitrite (ONOO-). Nitric oxide is the only biological molecule produced in high enough concentrations to out-compete superoxide dismutase for superoxide. Peroxynitrite reacts relatively slowly with most biological molecules, making peroxynitrite a selective oxidant. Peroxynitrite modifies tyrosine in proteins to create nitrotyrosines, leaving a footprint detectable in vivo. Nitration of structural proteins, including neurofilaments and actin, can disrupt filament assembly with major pathological consequences. Antibodies to nitrotyrosine have revealed nitration in human atherosclerosis, myocardial ischemia, septic and distressed lung, inflammatory bowel disease, and amyotrophic lateral sclerosis.

Nitric oxide as a secretory product of mammalian cells

1992-09-01

Carl Nathan

Evolution has resorted to nitric oxide (NO), a tiny, reactive radical gas, to mediate both servoregulatory and cytotoxic functions. This article reviews how different forms of nitric oxide synthase help … Evolution has resorted to nitric oxide (NO), a tiny, reactive radical gas, to mediate both servoregulatory and cytotoxic functions. This article reviews how different forms of nitric oxide synthase help confer specificity and diversity on the effects of this remarkable signaling molecule.

Nitric oxide: physiology, pathophysiology, and pharmacology.

1991-06-01

Salvador Moncada , Richard Palmer , E.A. Higgs

Flow-mediated endothelial mechanotransduction

1995-07-01

Peter F. Davies

Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major … Mechanical forces associated with blood flow play important roles in the acute control of vascular tone, the regulation of arterial structure and remodeling, and the localization of atherosclerotic lesions. Major regulation of the blood vessel responses occurs by the action of hemodynamic shear stresses on the endothelium. The transmission of hemodynamic forces throughout the endothelium and the mechanotransduction mechanisms that lead to biophysical, biochemical, and gene regulatory responses of endothelial cells to hemodynamic shear stresses are reviewed.

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Superoxide Dismutase

1969-11-01

Joe M. McCord , Irwin Fridovich

An enzyme which catalyzes the dismutation of superoxide radicals (O2·- + O2·- + 2H+ → O2 + H2O2) has been purified by a simple procedure from bovine erythrocytes. This enzyme, … An enzyme which catalyzes the dismutation of superoxide radicals (O2·- + O2·- + 2H+ → O2 + H2O2) has been purified by a simple procedure from bovine erythrocytes. This enzyme, called superoxide dismutase, contains 2 eq of copper per mole of enzyme. The copper may be reversibly removed, and it is required for activity. Superoxide dismutase has been shown to be identical with the previously described copper-containing erythrocuprein (human) and hemocuprein (bovine). Stable solutions of the superoxide radical were generated by the electrolytic reduction of O2 in an aprotic solvent, dimethylformamide. Slow infusion of such solutions into buffered aqueous media permitted the demonstration that O2·- can reduce ferricytochrome c and tetranitromethane, and that superoxide dismutase, by competing for the superoxide radicals, can markedly inhibit these reactions. Superoxide dismutase was used to show that the oxidation of epinephrine to adrenochrome by milk xanthine oxidase is mediated by the superoxide radical. An assay of several tissues indicates that superoxide dismutase is widely distributed within mammalian organisms.

A Rapid, Simple Spectrophotometric Method for Simultaneous Detection of Nitrate and Nitrite

2001-02-01

Katrina M. Miranda , Michael Graham Espey , David A. Wink

Localization of nitric oxide synthase indicating a neural role for nitric oxide

1990-10-25

David S. Bredt , Paul M. Hwang , Solomon H. Snyder

Peroxynitrite-induced membrane lipid peroxidation: The cytotoxic potential of superoxide and nitric oxide

1991-08-01

Rafael Radí , Joseph S. Beckman , Kenneth M. Bush +1 more

Nitric oxide synthases: Roles, tolls, and controls

1994-09-01

Carl Nathan , Q W Xie

Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. Contribution to alterations of vasomotor tone.

1996-04-15

Sanjay Rajagopalan , Stephan Kurz , Thomas Münzel +4 more

We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 … We tested the hypothesis that angiotensin II-induced hypertension is associated with an increase in vascular .O2- production, and characterized the oxidase involved in this process. Infusion of angiotensin II (0.7 mg/kg per d) increased systolic blood pressure and doubled vascular .O2- production (assessed by lucigenin chemiluminescence), predominantly from the vascular media. NE infusion (2.75 mg/kg per d) produced a similar degree of hypertension, but did not increase vascular .O2- production. Studies using various enzyme inhibitors and vascular homogenates suggested that the predominant source of .O2- activated by angiotensin II infusion is an NADH/NADPH-dependent, membrane-bound oxidase. Angiotensin II-, but not NE-, induced hypertension was associated with impaired relaxations to acetylcholine, the calcium ionophore A23187, and nitroglycerin. These relaxations were variably corrected by treatment of vessels with liposome-encapsulated superoxide dismutase. When Losartan was administered concomitantly with angiotensin II, vascular .O2- production and relaxations were normalized, demonstrating a role for the angiotensin type-1 receptor in these processes. We conclude that forms of hypertension associated with elevated circulating levels of angiotensin II may have unique vascular effects not shared by other forms of hypertension because they increase vascular smooth muscle .O2- production via NADH/NADPH oxidase activation.

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The human endothelin family: three structurally and pharmacologically distinct isopeptides predicted by three separate genes.

1989-04-01

Akiko Inoue , Masashi Yanagisawa , Sadao Kimura +4 more

Three distinct human endothelin-related genes were cloned by screening a genomic DNA library under a low hybridization stringency with a synthetic oligonucleotide probe encoding a portion of the endothelin sequence. … Three distinct human endothelin-related genes were cloned by screening a genomic DNA library under a low hybridization stringency with a synthetic oligonucleotide probe encoding a portion of the endothelin sequence. Genomic Southern blot analysis with the same oligonucleotide probe showed three corresponding chromosomal loci not only in the human genome but also in porcine and rat genomes. The nucleotide sequences of the three human genes were highly conserved within the regions encoding the 21-residue (mature) endothelins, in spite of the fact that the immediately upstream exon sequences, which encode a part of the propeptides, retained little similarity. Moreover, each of the human genes predicted a putative 21-residue peptide, similar to but distinct from each other: (i) the "classical" endothelin (ET-1), (ii) [Trp6,Leu7]endothelin (ET-2), and (iii) [Thr2,Phe4,Thr5,Tyr6, Lys7,Tyr14]endothelin (ET-3). Synthetic ET-1, ET-2, and ET-3 were prepared according to the deduced amino acid sequences, and the biological activities were assayed by contraction of isolated porcine coronary artery strips and by intravenous injection to anesthetized rats. All these synthetic peptides produced strong vasoconstrictor and pressor responses. However, the quantitative profiles of the pharmacological activities were considerably different among the three isopeptides, suggesting the possible existence of endothelin receptor subtypes.

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Nitric oxide mediates glutamate neurotoxicity in primary cortical cultures.

1991-07-15

Valina L. Dawson , Ted M. Dawson , Edythe D. London +2 more

Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide … Nitric oxide (NO) mediates several biological actions, including relaxation of blood vessels, cytotoxicity of activated macrophages, and formation of cGMP by activation of glutamate receptors in cerebellar slices. Nitric oxide synthase (EC 1.14.23.-) immunoreactivity is colocalized with nicotinamide adenine di-nucleotide phosphate diaphorase in neurons that are uniquely resistant to toxic insults. We show that the nitric oxide synthase inhibitors, N omega-nitro-L-arginine (EC50 = 20 microM) and N omega-monomethyl-L-arginine (EC50 = 170 microM), prevent neurotoxicity elicited by N-methyl-D-aspartate and related excitatory amino acids. This effect is competitively reversed by L-arginine. Depletion of the culture medium of arginine by arginase or arginine-free growth medium completely attenuates N-methyl-D-aspartate toxicity. Sodium nitroprusside, which spontaneously releases NO, produces dose-dependent cell death that parallels cGMP formation. Hemoglobin, which complexes NO, prevents neurotoxic effects of both N-methyl-D-aspartate and sodium nitroprusside. These data establish that NO mediates the neurotoxicity of glutamate.

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Nitric oxide synthases: regulation and function

2011-09-01

Ulrich Förstermann , William C. Sessa

Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require … Nitric oxide (NO), the smallest signalling molecule known, is produced by three isoforms of NO synthase (NOS; EC 1.14.13.39). They all utilize l-arginine and molecular oxygen as substrates and require the cofactors reduced nicotinamide-adenine-dinucleotide phosphate (NADPH), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN), and (6R-)5,6,7,8-tetrahydrobiopterin (BH4). All NOS bind calmodulin and contain haem. Neuronal NOS (nNOS, NOS I) is constitutively expressed in central and peripheral neurons and some other cell types. Its functions include synaptic plasticity in the central nervous system (CNS), central regulation of blood pressure, smooth muscle relaxation, and vasodilatation via peripheral nitrergic nerves. Nitrergic nerves are of particular importance in the relaxation of corpus cavernosum and penile erection. Phosphodiesterase 5 inhibitors (sildenafil, vardenafil, and tadalafil) require at least a residual nNOS activity for their action. Inducible NOS (NOS II) can be expressed in many cell types in response to lipopolysaccharide, cytokines, or other agents. Inducible NOS generates large amounts of NO that have cytostatic effects on parasitic target cells. Inducible NOS contributes to the pathophysiology of inflammatory diseases and septic shock. Endothelial NOS (eNOS, NOS III) is mostly expressed in endothelial cells. It keeps blood vessels dilated, controls blood pressure, and has numerous other vasoprotective and anti-atherosclerotic effects. Many cardiovascular risk factors lead to oxidative stress, eNOS uncoupling, and endothelial dysfunction in the vasculature. Pharmacologically, vascular oxidative stress can be reduced and eNOS functionality restored with renin- and angiotensin-converting enzyme-inhibitors, with angiotensin receptor blockers, and with statins.

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A modified uronic acid carbazole reaction

1962-10-01

Thomas Bitter , H. M. Muir

Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor

1987-06-01

Richard Palmer , Anthony G. Ferrige , Salvador Moncada

Cloned and expressed nitric oxide synthase structurally resembles cytochrome P-450 reductase

1991-06-01

David S. Bredt , Paul M. Hwang , Charles E. Glatt +3 more

Biochemistry of Nitric Oxide and Its Redox-Activated Forms

1992-12-18

Jonathan S. Stamler , David J. Singel , Joseph Loscalzo

Nitric oxide (NO ⋅ ), a potentially toxic molecule, has been implicated in a wide range of biological functions. Details of its biochemistry, however, remain poorly understood. The broader chemistry … Nitric oxide (NO ⋅ ), a potentially toxic molecule, has been implicated in a wide range of biological functions. Details of its biochemistry, however, remain poorly understood. The broader chemistry of nitrogen monoxide (NO) involves a redox array of species with distinctive properties and reactivities: NO + (nitrosonium), NO ⋅ , and NO - (nitroxyl anion). The integration of this chemistry with current perspectives of NO biology illuminates many aspects of NO biochemistry, including the enzymatic mechanism of synthesis, the mode of transport and targeting in biological systems, the means by which its toxicity is mitigated, and the function-regulating interaction with target proteins.

Endothelium-derived relaxing factor release on activation of NMDA receptors suggests role as intercellular messenger in the brain

1988-11-01

John Garthwaite , Sarah L. Charles , Russ Chess‐Williams

Nitric oxide: an endogenous modulator of leukocyte adhesion.

1991-06-01

Paul Kubes , Motohisa Suzuki , D. Neil Granger

The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors … The objective of this study was to determine whether endogenous nitric oxide (NO) inhibits leukocyte adhesion to vascular endothelium. This was accomplished by superfusing a cat mesenteric preparation with inhibitors of NO production, NG-monomethyl-L-arginine (L-NMMA) or NG-nitro-L-arginine methyl ester (L-NAME), and observing single (30-microns diameter) venules by intravital video microscopy. Thirty minutes into the superfusion period the number of adherent and emigrated leukocytes, the erythrocyte velocity, and the venular diameter were measured; venular blood flow and shear rate were calculated from the measured parameters. The contribution of the leukocyte adhesion glycoprotein CD11/CD18 was determined using the CD18-specific monoclonal antibody IB4. Both inhibitors of NO production increased leukocyte adherence more than 15-fold. Leukocyte emigration was also enhanced, whereas venular shear rate was reduced by nearly half. Antibody IB4 abolished the leukocyte adhesion induced by L-NMMA and L-NAME. Incubation of isolated cat neutrophils with L-NMMA, but not L-NAME, resulted in direct upregulation of CD11/CD18 as assessed by flow cytometry. Decrements in venular shear rate induced by partial occlusion of the superior mesenteric artery in untreated animals revealed that only a minor component of L-NAME-induced leukocyte adhesion was shear rate-dependent. The L-NAME-induced adhesion was inhibited by L-arginine but not D-arginine. These data suggest that endothelium-derived NO may be an important endogenous modulator of leukocyte adherence and that impairment of NO production results in a pattern of leukocyte adhesion and emigration that is characteristic of acute inflammation.

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Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells.

1989-05-01

Uttam Garg , Aviv Hassid

Endothelium-derived relaxing factor has been recently identified as nitric oxide. The purpose of this study was to determine if vasodilator drugs that generate nitric oxide inhibit vascular smooth muscle mitogenesis … Endothelium-derived relaxing factor has been recently identified as nitric oxide. The purpose of this study was to determine if vasodilator drugs that generate nitric oxide inhibit vascular smooth muscle mitogenesis and proliferation in culture. Three chemically dissimilar vasodilators, sodium nitroprusside, S-nitroso-N-acetylpenicillamine and isosorbide dinitrate, dose-dependently inhibited serum-induced thymidine incorporation by rat aortic smooth muscle cells. Moreover, 8-bromo-cGMP mimicked the antimitogenic effect of the nitric oxide-generating drugs. The antimitogenic effect of S-nitroso-N-acetylpenicillamine was inhibited by hemoglobin and potentiated by superoxide dismutase, supporting the view that nitric oxide was the ultimate effector. Sodium nitroprusside and S-nitroso-N-acetylpenicillamine significantly decreased the proliferation of vascular smooth muscle cells. Moreover, the inhibition of mitogenesis and proliferation was shown to be independent of cell damage, as documented by several criteria of cell viability. These results suggest that endogenous nitric oxide may function as a modulator of vascular smooth muscle cell mitogenesis and proliferation, by a cGMP-mediated mechanism.

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Vascular endothelial cells synthesize nitric oxide from L-arginine

1988-06-01

Richard Palmer , D. Ashton , Salvador Moncada

Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide.

1990-02-01

Joseph S. Beckman , ThomasJ Beckman , Jake Y. Chen +2 more

Superoxide dismutase reduces injury in many disease processes, implicating superoxide anion radical (O2-.) as a toxic species in vivo. A critical target of superoxide may be nitric oxide (NO.) produced … Superoxide dismutase reduces injury in many disease processes, implicating superoxide anion radical (O2-.) as a toxic species in vivo. A critical target of superoxide may be nitric oxide (NO.) produced by endothelium, macrophages, neutrophils, and brain synaptosomes. Superoxide and NO. are known to rapidly react to form the stable peroxynitrite anion (ONOO-). We have shown that peroxynitrite has a pKa of 7.49 +/- 0.06 at 37 degrees C and rapidly decomposes once protonated with a half-life of 1.9 sec at pH 7.4. Peroxynitrite decomposition generates a strong oxidant with reactivity similar to hydroxyl radical, as assessed by the oxidation of deoxyribose or dimethyl sulfoxide. Product yields indicative of hydroxyl radical were 5.1 +/- 0.1% and 24.3 +/- 1.0%, respectively, of added peroxynitrite. Product formation was not affected by the metal chelator diethyltriaminepentaacetic acid, suggesting that iron was not required to catalyze oxidation. In contrast, desferrioxamine was a potent, competitive inhibitor of peroxynitrite-initiated oxidation because of a direct reaction between desferrioxamine and peroxynitrite rather than by iron chelation. We propose that superoxide dismutase may protect vascular tissue stimulated to produce superoxide and NO. under pathological conditions by preventing the formation of peroxynitrite.

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Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure

1992-03-01

A. Leone , S. Moncada , Patrick Vallance +2 more

Cloning and expression of a cDNA encoding an endothelin receptor

1990-12-01

Hiroshi Arai , Seiji Hori , Ichiro Aramori +2 more

Isolation of nitric oxide synthetase, a calmodulin-requiring enzyme.

1990-01-01

David S. Bredt , Solomon H. Snyder

Nitric oxide mediates vascular relaxing effects of endothelial cells, cytotoxic actions of macrophages and neutrophils, and influences of excitatory amino acids on cerebellar cyclic GMP. Its enzymatic formation from arginine … Nitric oxide mediates vascular relaxing effects of endothelial cells, cytotoxic actions of macrophages and neutrophils, and influences of excitatory amino acids on cerebellar cyclic GMP. Its enzymatic formation from arginine by a soluble enzyme associated with stoichiometric production of citrulline requires NADPH and Ca2+. We show that nitric oxide synthetase activity requires calmodulin. Utilizing a 2',5'-ADP affinity column eluted with NADPH, we have purified nitric oxide synthetase 6000-fold to homogeneity from rat cerebellum. The purified enzyme migrates as a single 150-kDa band on SDS/PAGE, and the native enzyme appears to be a monomer.

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A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds

1993-08-01

Stuart A. Lipton , Yun‐Beom Choi , Zhuo‐Hua Pan +6 more

Glutamate, nitric oxide and cell-cell signalling in the nervous system

1991-02-01

John Garthwaite

Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.

1987-12-01

L J Ignarro , Georgette M. Buga , K S Wood +2 more

The objective of this study was to determine whether nitric oxide (NO) is responsible for the vascular smooth muscle relaxation elicited by endothelium-derived relaxing factor (EDRF). EDRF is an unstable … The objective of this study was to determine whether nitric oxide (NO) is responsible for the vascular smooth muscle relaxation elicited by endothelium-derived relaxing factor (EDRF). EDRF is an unstable humoral substance released from artery and vein that mediates the action of endothelium-dependent vasodilators. NO is an unstable endothelium-independent vasodilator that is released from vasodilator drugs such as nitroprusside and glyceryl trinitrate. We have repeatedly observed that the actions of NO on vascular smooth muscle closely resemble those of EDRF. In the present study the vascular effects of EDRF released from perfused bovine intrapulmonary artery and vein were compared with the effects of NO delivered by superfusion over endothelium-denuded arterial and venous strips arranged in a cascade. EDRF was indistinguishable from NO in that both were labile (t1/2 = 3-5 sec), inactivated by pyrogallol or superoxide anion, stabilized by superoxide dismutase, and inhibited by oxyhemoglobin or potassium. Both EDRF and NO produced comparable increases in cyclic GMP accumulation in artery and vein, and this cyclic GMP accumulation was inhibited by pyrogallol, oxyhemoglobin, potassium, and methylene blue. EDRF was identified chemically as NO, or a labile nitroso species, by two procedures. First, like NO, EDRF released from freshly isolated aortic endothelial cells reacted with hemoglobin to yield nitrosylhemoglobin. Second, EDRF and NO each similarly promoted the diazotization of sulfanilic acid and yielded the same reaction product after coupling with N-(1-naphthyl)-ethylenediamine. Thus, EDRF released from artery and vein possesses identical biological and chemical properties as NO.

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Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor

1986-04-01

Ryszard J. Gryglewski , Richard Palmer , Salvador Moncada

Angiotensin II stimulates NADH and NADPH oxidase activity in cultured vascular smooth muscle cells.

1994-06-01

Kathy K. Griendling , C A Minieri , Jeremy D. Ollerenshaw +1 more

The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to … The signaling pathways involved in the long-term metabolic effects of angiotensin II (Ang II) in vascular smooth muscle cells are incompletely understood but include the generation of molecules likely to affect oxidase activity. We examined the ability of Ang II to stimulate superoxide anion formation and investigated the identity of the oxidases responsible for its production. Treatment of vascular smooth muscle cells with Ang II for 4 to 6 hours caused a 2.7 +/- 0.4-fold increase in intracellular superoxide anion formation as detected by lucigenin assay. This superoxide appeared to result from activation of both the NADPH and NADH oxidases. NADPH oxidase activity increased from 3.23 +/- 0.61 to 11.80 +/- 1.72 nmol O2-/min per milligram protein after 4 hours of Ang II, whereas NADH oxidase activity increased from 16.76 +/- 2.13 to 45.00 +/- 4.57 nmol O2-/min per milligram protein. The NADPH oxidase activity was stimulated by exogenous phosphatidic and arachidonic acids and was partially inhibited by the specific inhibitor diphenylene iodinium. NADH oxidase activity was increased by arachidonic and linoleic acids, was insensitive to exogenous phosphatidic acid, and was inhibited by high concentrations of quinacrine. Both of these oxidases appear to reside in the plasma membrane, on the basis of migration of the activity after cellular fractionation and their apparent insensitivity to the mitochondrial poison KCN. These observations suggest that Ang II specifically activates enzyme systems that promote superoxide generation and raise the possibility that these pathways function as second messengers for long-term responses, such as hypertrophy or hyperplasia.

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Nitric oxide synthases: structure, function and inhibition

2001-08-01

W. Alderton , Chris E. Cooper , Richard G. Knowles

This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our … This review concentrates on advances in nitric oxide synthase (NOS) structure, function and inhibition made in the last seven years, during which time substantial advances have been made in our understanding of this enzyme family. There is now information on the enzyme structure at all levels from primary (amino acid sequence) to quaternary (dimerization, association with other proteins) structure. The crystal structures of the oxygenase domains of inducible NOS (iNOS) and vascular endothelial NOS (eNOS) allow us to interpret other information in the context of this important part of the enzyme, with its binding sites for iron protoporphyrin IX (haem), biopterin, l-arginine, and the many inhibitors which interact with them. The exact nature of the NOS reaction, its mechanism and its products continue to be sources of controversy. The role of the biopterin cofactor is now becoming clearer, with emerging data implicating one-electron redox cycling as well as the multiple allosteric effects on enzyme activity. Regulation of the NOSs has been described at all levels from gene transcription to covalent modification and allosteric regulation of the enzyme itself. A wide range of NOS inhibitors have been discussed, interacting with the enzyme in diverse ways in terms of site and mechanism of inhibition, time-dependence and selectivity for individual isoforms, although there are many pitfalls and misunderstandings of these aspects. Highly selective inhibitors of iNOS versus eNOS and neuronal NOS have been identified and some of these have potential in the treatment of a range of inflammatory and other conditions in which iNOS has been implicated.

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Nitric Oxide and Peroxynitrite in Health and Disease

2007-01-01

Pál Pacher , Joseph S. Beckman , Lucas Liaudet

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology … The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

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NAD(P)H Oxidase

2000-03-17

Kathy K. Griendling , Dan C. Sorescu , Masuko Ushio‐Fukai

Abstract —Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The … Abstract —Reactive oxygen species have emerged as important molecules in cardiovascular function. Recent work has shown that NAD(P)H oxidases are major sources of superoxide in vascular cells and myocytes. The biochemical characterization, activation paradigms, structure, and function of this enzyme are now partly understood. Vascular NAD(P)H oxidases share some, but not all, characteristics of the neutrophil enzyme. In response to growth factors and cytokines, they produce superoxide, which is metabolized to hydrogen peroxide, and both of these reactive oxygen species serve as second messengers to activate multiple intracellular signaling pathways. The vascular NAD(P)H oxidases have been found to be essential in the physiological response of vascular cells, including growth, migration, and modification of the extracellular matrix. They have also been linked to hypertension and to pathological states associated with uncontrolled growth and inflammation, such as atherosclerosis.

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Endothelial Dysfunction in Cardiovascular Diseases: The Role of Oxidant Stress

2000-11-10

Hua Cai , David G. Harrison

Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) … Accumulating evidence suggests that oxidant stress alters many functions of the endothelium, including modulation of vasomotor tone. Inactivation of nitric oxide (NO(.)) by superoxide and other reactive oxygen species (ROS) seems to occur in conditions such as hypertension, hypercholesterolemia, diabetes, and cigarette smoking. Loss of NO(.) associated with these traditional risk factors may in part explain why they predispose to atherosclerosis. Among many enzymatic systems that are capable of producing ROS, xanthine oxidase, NADH/NADPH oxidase, and uncoupled endothelial nitric oxide synthase have been extensively studied in vascular cells. As the role of these various enzyme sources of ROS become clear, it will perhaps be possible to use more specific therapies to prevent their production and ultimately correct endothelial dysfunction.

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NITRIC OXIDE AND MACROPHAGE FUNCTION

1997-04-01

John D. MacMicking , Q W Xie , Carl Nathan

At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding … At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.

Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor

1990-12-01

Takeshi Sakurai , Masashi Yanagisawa , Yoh Takuwat +4 more

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A novel potent vasoconstrictor peptide produced by vascular endothelial cells

1988-03-01

Masashi Yanagisawa , Hiroki Kurihara , Sadao Kimura +6 more

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The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine

1980-11-01

Robert F. Furchgott , John V. Zawadzki

The L-Arginine-Nitric Oxide Pathway

1993-12-30

Franklin H. Epstein , Salvador Moncada , Annie Higgs

The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized … The discovery that mammalian cells generate nitric oxide, a gas previously considered to be merely an atmospheric pollutant, is providing important information about many biologic processes. Nitric oxide is synthesized from the amino acid L-arginine by a family of enzymes, the nitric oxide synthases, through a hitherto unrecognized metabolic route -- namely, the L-arginine-nitric oxide pathway18.The synthesis of nitric oxide by vascular endothelium is responsible for the vasodilator tone that is essential for the regulation of blood pressure. In the central nervous system nitric oxide is a neurotransmitter that underpins several functions, including the formation of memory. . . .

Paradoxical Vasoconstriction Induced by Acetylcholine in Atherosclerotic Coronary Arteries

1986-10-23

Paul L. Ludmer , Andrew P. Selwyn , Thomas Shook +4 more

Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, … Acetylcholine is believed to dilate normal blood vessels by promoting the release of a vasorelaxant substance from the endothelium (endothelium-derived relaxing factor). By contrast, if the endothelium is removed experimentally, acetylcholine constricts blood vessels. We tested the hypothesis that muscarinic cholinergic vasodilation is impaired in coronary atherosclerosis. Graded concentrations of acetylcholine and, for comparison, the nonendothelial-dependent vasodilator nitroglycerin were infused into the left anterior descending artery of eight patients with advanced coronary stenoses (>50 percent narrowing), four subjects with angiographically normal coronary arteries, and six patients with mild coronary atherosclerosis (<20 percent narrowing). Vascular responses were evaluated by quantitative angiography. In several segments each of four normal coronary arteries, acetylcholine caused a dose-dependent dilation from a control diameter of 1.94±0.16 mm to 2.16±0.15 mm with the maximal acetylcholine dose (P<0.01). In contrast, all eight of the arteries with advanced stenoses showed dose-dependent constriction, from 1.05±0.05 to 0.32±0.16 mm at the highest concentration of acetylcholine (P<0.01), with temporary occlusion in five. Five of six vessels with minimal disease also constricted in response to acetylcholine. All vessels dilated in response to nitroglycerin, however. We conclude that paradoxical vasoconstriction induced by acetylcholine occurs early as well as late in the course of coronary atherosclerosis. Our preliminary findings suggest that the abnormal vascular response to acetylcholine may represent a defect in endothelial vasodilator function, and may be important in the pathogenesis of coronary vasospasm. (N Engl J Med 1986; 315:1046–51.)

Abnormal Endothelium-Dependent Vascular Relaxation in Patients with Essential Hypertension

1990-07-05

Julio A. Panza , Arshed A. Quyyumi , John E. Brush +1 more

Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic … Endothelium regulates vascular tone by influencing the contractile activity of vascular smooth muscle. This regulatory effect of the endothelium on blood vessels has been shown to be impaired in atherosclerotic arteries in humans and animals and in animal models of hypertension.To determine whether patients with essential hypertension have an endothelium-dependent abnormality in vascular relaxation, we studied the response of the forearm vasculature to acetylcholine (an endothelium-dependent vasodilator) and sodium nitroprusside (a direct dilator of smooth muscle) in 18 hypertensive patients (mean age [+/- SD], 50.7 +/- 10 years; 10 men and 8 women) two weeks after the withdrawal of antihypertensive medications and in 18 normal controls (mean age, 49.9 +/- 9; 9 men and 9 women). The drugs were infused at increasing concentrations into the brachial artery, and the response in forearm blood flow was measured by strain-gauge plethysmography.The basal forearm blood flow was similar in the patients and controls (mean +/- SD, 3.4 +/- 1.3 and 3.7 +/- 0.8 ml per minute per 100 ml of forearm tissue, respectively; P not significant). The responses of blood flow and vascular resistance to acetylcholine were significantly reduced in the hypertensive patients (P less than 0.0001); maximal forearm flow was 9.1 +/- 5 ml per minute per 100 ml in the patients and 20.0 +/- 8 ml per minute per 100 ml in the controls (P less than 0.0002). However, there were no significant differences between groups in the responses of blood flow and vascular resistance to sodium nitroprusside. Because the vasodilator effect of acetylcholine might also be due to presynaptic inhibition of the release of norepinephrine by adrenergic nerve terminals, the effect of acetylcholine was assessed during phentolamine-induced alpha-adrenergic blockade. Under these conditions, it was also evident that the responses to acetylcholine were significantly blunted in the hypertensive patients (P less than 0.03).Endothelium-mediated vasodilation is impaired in patients with essential hypertension. This defect may play an important part in the functional abnormalities of resistance vessels that are observed in hypertensive patients.

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Nitric oxide synthases: structure, function and inhibition

2001-07-25

W. Alderton , Chris E. Cooper , Richard G. Knowles

A FRET-based ratiometric fluorescence sensor for peroxynitrite detection and its application in living cells, zebrafish, and ultraviolet-induced mouse models imaging

2025-06-24

Yu Pan , Xia Gu , Yaping Yuan +6 more | Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy

Hydrochlorothiazide

2025-06-21

| Reactions Weekly

Nitric-oxide

2025-06-21

| Reactions Weekly

Lorazepam/nitroglycerin

2025-06-21

| Reactions Weekly

Hydrochlorothiazide

2025-06-21

| Reactions Weekly

Vericiguat, a Soluble Guanylate Cyclase Stimulator Approved for Heart Failure Treatment

2025-06-20

Mahmoud Kallash , William H. Frishman | Cardiology in Review

Heart failure (HF) is an emerging, global epidemic associated with substantial morbidity and mortality. In recent years, significant advancements have been made in the development of pharmacotherapies that provide mortality … Heart failure (HF) is an emerging, global epidemic associated with substantial morbidity and mortality. In recent years, significant advancements have been made in the development of pharmacotherapies that provide mortality benefits in HF. Research into the pathophysiology of HF with reduced ejection fraction (HFrEF) has identified significant abnormalities in the critical nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) cascade. In HFrEF, there is reduced NO bioavailability, impaired sGC activity, and upregulation of phosphodiesterase activity, all causing a significant decrease in cGMP, impairing vasodilation and increasing cardiac fibrosis and hypertrophy. Vericiguat, an sGC stimulator, was developed to potentially harness the therapeutic efficacy of this pathway. In a major clinical trial, vericiguat use in patients with HFrEF on guideline-directed medical therapy and recent worsening of HF resulted in a significant decrease in the composite of death from cardiovascular causes or first hospitalization for HF compared with placebo. Current American Heart Association guidelines recommend that in selected high-risk patients with HFrEF and recent worsening of HF already on guideline-directed medical therapy, initiation of the oral sGC stimulator vericiguat may be considered to reduce HF hospitalization and cardiovascular death. However, while vericiguat represents a major accomplishment in capitalizing on the therapeutic potential of the NO-sGC-cGMP pathway, there remain significant challenges regarding the personalization of therapy and identification of the phenotype of the HFrEF population that most benefits from vericiguat therapy. Further research is currently underway to identify vericiguat’s potential role in the treatment of chronic stable HFrEF without recent worsening of HF.

Allotriophagy in a Patient With Schizophrenia: A Case Report

2025-06-19

Sarah B Guttman , Manlio Alessi , Enzo S Carioni +6 more | Cureus

Abstract P1-06-07: APOE4 impairs the cardiac stress response to doxorubicin through defective M2 macrophage activation and tissue repair transcription pathways

2025-06-13

Nanette H. Bishopric , Harshul Pandit , Adam Ikeda +4 more | Clinical Cancer Research

Abstract Background: The human apolipoprotein E (APOE) gene has three major allelic variants: APOE3, APOE4, and APOE2. Carriers of the APOE4 allele are at high risk for Alzheimer’s and other … Abstract Background: The human apolipoprotein E (APOE) gene has three major allelic variants: APOE3, APOE4, and APOE2. Carriers of the APOE4 allele are at high risk for Alzheimer’s and other neurodegenerative disorders and exhibit elevated oxidative stress in the central nervous system. Recently, we observed that mice expressing the human APOE4 allele are predisposed to cardiac damage induced by doxorubicin (DOX), a potent and widely used breast cancer therapeutic. How APOE4 contributes to oxidative stress-related tissue damage remains poorly understood. Objective: To identify mechanisms of APOE4-mediated vulnerability to DOX cardiotoxicity. Methods: C57Bl/6 mice (5-8 mo and 14-18 mo, male and female) with human APOE3 or APOE4 homozygous knock-in (=APOE3 and APOE4, respectively) received a single IP injection of saline (Control) or DOX (10 mg/kg) and monitored between 3-45 days afterward. Cardiac function was quantitated using echocardiography (Vevo 3100) at baseline and during the study. TUNEL assays were used to identify apoptotic cells. Collagen was imaged by Masson’s Trichrome staining. Myocardial protein and RNA were extracted from the left ventricle and subjected to immunoblotting, IHC, real-time PCR, and RNASeq. Transcriptomic data were analyzed using Gene Set Enrichment Analysis (GSEA) for pathway analysis and CIBERSORTx for deconvolution of myocardial immune cell subtypes. Results: At baseline, no difference in cardiac function was observed between the 2 mouse lines. Following DOX treatment, APOE4 mice had greater declines in left ventricular ejection fraction, heart weight, and more myocyte apoptosis compared with age-matched APOE3 mice (all p&lt;0.05). APOE4 also conferred more age-associated myocardial collagen and cardiomyocyte apoptosis than APOE3, and higher myocardial levels of 4-HNE (4-hydroxy-2-nonenal), an oxidative stress byproduct. Surprisingly, APOE4 mice had a marked reduction in immunoglobulin production and age-dependent IgG deposition in the myocardium compared with both APOE3 and wt mice (p= 0.002, E4 vs. E3 at 17 mo). The transcriptomic analysis confirmed defective activation of TGF-beta, TNF-alpha, Myc, and p53 pathway genes in APOE4 mice after DOX, as well as a defective tissue repair response. In APOE3 myocardium, mRNAs encoding neuregulin (Nrg1), a key cardiac survival/repair factor, and multiple cardiac-specific contractile proteins were induced at d3 after DOX; this response was markedly attenuated in APOE4 mice. CIBERSORTx analysis for 22 distinct immune cell types showed an increase in activated M2 macrophages after DOX in APOE3, but not in APOE4 mice. Western and immunohistochemical analyses confirmed increased CD206, a specific M2 macrophage biomarker, in APOE3 but not in APOE4 mice after DOX (p&lt;0.05.) Of note, M2 macrophages increased with age in both wt and APOE3 mice, but not in APOE4 mice (p&lt;0.05, E3 vs. E4, 17 mo.). Conclusion: Our results suggest that the APOE4 allele may confer increased vulnerability to DOX-induced and age-mediated cardiac damage through specific impairment of post-injury repair responses involving M2 macrophage polarization and activation. Whether this is related to known APOE allelic differences in lipoprotein transport or innate immunity functions remains to be determined, as does potential relevance to chemotherapy and other types of cardiac injury in humans. Citation Format: Nanette Bishopric, Harshul Pandit, Adam Ikeda, Kyle Korolowicz, G. William Rebeck, Olga Rodriguez, Marc E. Lippman, Nanette H. Bishopric. APOE4 impairs the cardiac stress response to doxorubicin through defective M2 macrophage activation and tissue repair transcription pathways [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P1-06-07.

Asymmetric dimethylarginine (ADMA) and citrulline are risk factors for cardiovascular disease independently of both estimated and measured GFR

2025-06-12

Nikoline B. Rinde , Toralf Melsom , Ole‐Martin Fuskevåg +2 more | Clinical Kidney Journal

Abstract Background Nitric oxide (NO) is crucial for endothelial dysfunction, and its deficiency is linked to cardiovascular disease (CVD) and impaired kidney function. While research has explored NO-metabolism in individuals … Abstract Background Nitric oxide (NO) is crucial for endothelial dysfunction, and its deficiency is linked to cardiovascular disease (CVD) and impaired kidney function. While research has explored NO-metabolism in individuals with kidney disease, diabetes mellitus (DM), or CVD, the relationship in healthy individuals remains unclear. Studies using estimated glomerular filtration rate (GFR) for kidney function may introduce non-GFR-related factors confounding the results. We investigated the association between NO-related biomarkers and CVD outcomes in a healthy population, comparing adjustments using estimated GFR (eGFR) and measured GFR (mGFR). Methods This 14-year longitudinal study evaluated 1,575 healthy, middle-aged participants without preexisting DM, CVD, or kidney disease in the Renal Iohexol Clearance Survey (RENIS). Cox regression models assessed the effects of asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), arginine, citrulline, and ornithine levels on CVD incidence and all-cause mortality. Analyses were adjusted for GFR using mGFR by iohexol clearance, eGFR based on serum creatinine (eGFRCrea), or cystatin C (eGFRCys). Results Elevated ADMA levels were associated with incident CVD across all GFR adjustment methods, with a hazard ratio (HR) of 1.21 (95% CI, 1.06-1.38) for mGFR. SDMA was associated with CVD when adjusting for eGFRCrea (HR 1.19; 95% CI, 1.03-1.38), not with mGFR or eGFRCys. Through all GFR methods, higher citrulline levels consistently correlated with CVD (HR, 1.17; 95% CI, 1.03-1.33 for mGFR). No biomarkers were linked to all-cause mortality. Conclusions In a healthy population, ADMA and citrulline were associated with incident CVD, regardless of the GFR adjustment method, while SDMA's association depended on the method used.

The protective mechanism of taurine deoxycholic acid (TCDCA) through LPAR1 regulation in Buga syndrome

2025-06-12

Zeyu Guan , Xiaogao Wang , Ran Lu +3 more | Research Square (Research Square)

<title>Abstract</title> The etiology of Budd-Chiari syndrome (BCS), an uncommon but clinically significant condition, remains unclear. Therefore, this study investigates how taurodeoxycholic acid (TCDCA) influences human umbilical vein endothelial cells (HUVECs) … <title>Abstract</title> The etiology of Budd-Chiari syndrome (BCS), an uncommon but clinically significant condition, remains unclear. Therefore, this study investigates how taurodeoxycholic acid (TCDCA) influences human umbilical vein endothelial cells (HUVECs) in BCS. Following TCDCA treatment, the proliferation, apoptosis, migration, inflammatory response, and angiogenesis of HUVECs were examined, along with the levels of cAMP. Transcriptomic sequencing was further performed. Silencing LPAR1 in HUVECs was performed to explore its functional role. The results revealed significantly higher LPAR1 levels in HUVECs compared to controls. Silencing LPAR1 inhibited cell proliferation, migration, inflammation, and angiogenesis, while promoting apoptosis and increasing cAMP levels. Clinical samples from BCS patients showed significant upregulation of LPAR1, supporting our in vitro findings. Our findings suggest that TCDCA plays a pivotal role in BCS by regulating LPAR1.

Efecto de la L-arginina sobre la dimetilarginina asimétrica y el óxido nítrico en la aterosclerosis

2025-06-10

Leticia Figueira | Revista de la Facultad de Farmacia

El endotelio juega un papel importante en el mantenimiento de la estructura y tono vascular. El óxido nítrico (NO) es uno de los principales mediadores vasoactivos derivados del endotelio y … El endotelio juega un papel importante en el mantenimiento de la estructura y tono vascular. El óxido nítrico (NO) es uno de los principales mediadores vasoactivos derivados del endotelio y es sintetizado a partir del aminoácido L-arginina (L-Arg). La dimetilarginina asimétrica (ADMA) es un inhibidor competitivo de la sintasa de óxido nítrico (NOS); por lo que inhibe la formación de NO. Esta molécula se le ha implicado como un factor de riesgo para la disfunción endotelial. En el presente estudio se evaluó el efecto de la administración oral de L-Arg sobre los niveles séricos de ADMA, NO y los productos de peroxidación lipídica (TBARS) y la formación de ateromas en conejos alimentados con una dieta enriquecida con colesterol. Para ello, 40 conejos machos Nueva Zelanda fueron divididos en cuatro grupos durante 12 semanas: Grupo 1 (control): Conejarina. Grupo 2: Conejarina suplementada con 0,5% p/p de colesterol. Grupo 3 (control L-Arg): Conejarina y L-Arg (1,5%, vía oral en el agua). Grupo 4: Conejarina suplementada con 0,5% colesterol y L-Arg. Se realizaron determinaciones séricas de colesterol y sus fracciones, ADMA, NO y TBARS al inicio y final del estudio (12ma semana de experimentación). Al final del estudio todos los conejos de cada grupo fueron sacrificados y se realizó estudio histológico de su aorta. Los resultados demuestran que a las 12 semanas, la dieta enriquecida con colesterol aumentó significativamente los niveles séricos de ADMA y TBARS y disminuyó los de NO (p<0,005). La L-Arg revirtió significativamente los cambios de las concentraciones séricas de ADMA y NO inducidas por la dieta enriquecida con colesterol (p<0,0050), pero no afectó significativamente los incrementos de TBARS. El tratamiento con L-Arg no tuvo mucho efecto sobre el grado de ateromas. En conclusión, la ADMA, NO y TBARS son marcadores séricos no invasivos de aterosclerosis; sugiriendo el papel del estrés oxidativo y la disfunción endotelial en la fisiopatología de esta enfermedad. Asimismo, la suplementación con L-Arg, puede ser útil para disminuir los niveles de ADMA y aumentar los de NO, posiblemente mejorando la disfunción endotelial.

The machinery of healthy vasodilatation: an overview

2025-06-06

Jana Pourová , Patrícia Dias , Milan Pour +1 more | Pflügers Archiv - European Journal of Physiology

Abstract Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. … Abstract Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.

BMAL1–HIF2A mediates diurnal cardioprotection during myocardial injury

2025-06-05

Elisa Martinif | Nature Cardiovascular Research

Detection and Analysis of Reactive Oxygen Species (ROS): Buffer Components Are Not Bystanders

2025-06-03

Shubham Bansal , Muskan Gori , Joanna Afokai Quaye +2 more | Analytical Chemistry

Reactive oxygen species (ROS) play critical roles in pathophysiological processes. Therefore, there is widespread interest in learning ROS concentrations under various conditions. However, literature numbers in ROS concentration vary significantly, … Reactive oxygen species (ROS) play critical roles in pathophysiological processes. Therefore, there is widespread interest in learning ROS concentrations under various conditions. However, literature numbers in ROS concentration vary significantly, and most cannot be readily compared against each other, largely because of the lack of understanding of the effects of various factors that significantly impact the experimental outcome. In this study, we examine an overlooked factor: the chemical reactivity of commonly used organic buffer molecules toward ROS and how such reactivity affects the results interpretation. Specifically, we examined HEPES, Tris, MES, citrate, ammonium acetate, and phosphate-buffered saline (PBS) and found that most organic buffer components can rapidly consume NaOCl (the second most abundant ROS) and/or directly interact with certain ROS probes such as a boronate for H2O2 determination, leading to significant errors in experimental findings and interpretations of results. For example, 20 mM HEPES, MES, ammonium acetate, and Tris are found to consume 1 mM hypochlorite within 1 s, leading to false negative results. Additionally, these organic buffer components have been found to cause false negative results in the detection of ONOO- when using a boronate-based probe. As such, these organic buffers should be avoided in the determination of ROS concentrations. We use these examples to draw attention to the profound effects of buffer components on ROS detection and examine chemistry issues in detail. We hope the findings described will lead to improved rigor in designing ROS experiments by considering factors that were previously considered as nothing but bystanders or benign.

Oxidative Stress and Endothelial Dysfunction: The Pathogenesis of Pediatric Hypertension

2025-06-03

Kyle J. Backston , James A. Morgan , Sagar B. Patel +3 more | International Journal of Molecular Sciences

Pediatric hypertension is increasingly recognized as a complex condition shaped by both systemic and cellular factors, with oxidative stress emerging as a key driver of vascular dysfunction. In both their … Pediatric hypertension is increasingly recognized as a complex condition shaped by both systemic and cellular factors, with oxidative stress emerging as a key driver of vascular dysfunction. In both their primary and secondary forms, reactive oxygen species (ROS) disrupt redox homeostasis, impair endothelial signaling, and promote inflammation and tissue remodeling. Metabolic dysregulation, renal pathology, and early-life stressors contribute to the accumulation of ROS through pathways involving NADPH oxidases, mitochondrial dysfunction, xanthine oxidase activity, and altered arginine metabolism. These mechanisms converge on the vasculature, diminishing nitric oxide bioavailability and promoting hypertensive phenotypes. Beyond disease initiation, redox imbalance influences the response to treatment, surgical outcomes, and long-term cardiovascular risk. By further elucidating these mechanisms, the complex relationship between oxidative stress, vascular biology, and blood pressure regulation in children may be more clearly defined and more effectively targeted in clinical management.

Formate yields protection from ischemic injury through a nitric oxide synthase-dependent increase in protein S-nitrosation

2025-06-01

Haley Garbus-Grant , Raihan Kabir , Oby Ebenebe +7 more | Journal of Molecular and Cellular Cardiology Plus

Sauerstoffmangel im Gehirn: Perfusion und Verfügbarkeit von A1-Adenosinrezeptoren

2025-06-01

Henning Weis , Eva-Maria Elmenhorst , David Elmenhorst +7 more | Flugmedizin · Tropenmedizin · Reisemedizin - FTR

Zusammenfassung In Nagern wurde beobachtet, dass der Neuromodulator Adenosin während Hypoxie im Gehirn freigesetzt wird und es vor Sauerstoffmangel und Überlastung schützt, indem Blutfluss, Stoffwechsel und elektrische Aktivität angepasst werden. … Zusammenfassung In Nagern wurde beobachtet, dass der Neuromodulator Adenosin während Hypoxie im Gehirn freigesetzt wird und es vor Sauerstoffmangel und Überlastung schützt, indem Blutfluss, Stoffwechsel und elektrische Aktivität angepasst werden. An 10 Probanden wurde geprüft, ob durch Hypoxie – einem Sauerstoffpartialdruck auf 5500 m entsprechend – die Verfügbarkeit von A1-Adenosinrezeptoren (A1AR) im menschlichen Gehirn entsprechend reduziert wird. Akute normobare Hypoxie führte im Gehirn zu einer Reduktion der A1AR-Verfügbarkeit, während sich die Perfusion und die Herzfrequenz erhöhten und sich die Reaktionsgeschwindigkeit verringerte. Unseres Wissens sind wir die erste Studie, die beim Menschen eine Verringerung der A1AR-Verfügbarkeit unter Hypoxie nachgewiesen hat. Die so reduzierte neuronale Aktivität bei gleichzeitig erhöhter Durchblutung wirken gemeinsam dem verringerten Sauerstoffangebot entgegen und könnte für zukünftige Gegenmaßnahmen eingesetzt werden.

C5ORF30/MACIR IS A ROBUST PROGNOSTIC MARKER IN DLBCL, AND MODULATES THE TUMOR MICROENVIRONMENT THROUGH HLA EXPRESSION

2025-06-01

Zi Xin Ong , M. M. Hoppe , S. Sridhar +7 more | Hematological Oncology

A novel acridine-based mitochondria-targeted near-infrared fluorescent probe for the detection of HOCl/ONOO- in vivo

2025-06-01

Yixuan Zhu , Caiyun Liu , Xiaodi Rong +6 more | Sensors and Actuators B Chemical

Exploring monoamine oxidase B in nitric oxide dysregulation and vascular disease

2025-06-01

Vijay Elipay , Atanu Mandal , Sanjiv Singh | European Journal of Pharmacology

Local ligand concentration gradients induced by the plasma membrane

2025-06-01

Ágnes Szabó , Gabriella Tóth , Tímea Szatmári +4 more | iScience

Modeling the effects of superoxide production on the cerebral blood flow

2025-06-01

David Terman , Yousef Hannawi | Journal of Theoretical Biology

Oxidative stress with the associated endothelial cell dysfunction is an important pathophysiological mechanism for the hypertension induced vascular dysfunction and end organ damage. The oxidant stress leads to the impairment … Oxidative stress with the associated endothelial cell dysfunction is an important pathophysiological mechanism for the hypertension induced vascular dysfunction and end organ damage. The oxidant stress leads to the impairment of nitric oxide synthesis, release and/or activity through multiple pathways which are all part of endothelial cells dysfunction. In the brain, this has been closely linked with the hypertension induced neurovascular dysfunction and impairment of cerebral blood flow regulation. The superoxide anion interacts with nitric oxide resulting in decreasing its bioavailability while generating the harmful perioxynitrite which contributes to the cellular oxidative damage. In this work, we develop a mathematical model representing the effects of nitric oxide and superoxide production and their interactions on changes of cerebral blood flow. Our model integrates and extends prior work through modeling the effects of nitric oxide and superoxide generation, diffusion and degradation on cerebral blood flow. Our results show that superoxide production attenuates the increase of cerebral blood flow mediated by nitric oxide production and explains the prior experimental observations. While strategies to increase nitric oxide production may alleviate the superoxide dependent decrease in cerebral blood flow, our model predicts an associated increase of perioxynitrite production leading to oxidative cellular injury. Our work provides a mathematical modeling platform that may be used to integrate the different cellular processes regulating the cellular response to oxidant stress. This platform can be utilized to test future therapeutics aiming to reduce the cerebrovascular oxidative stress related injuries and improve cerebral blood flow.

Inorganic Nitrate Stores, Astrocyte Metabolism and Brain Health: An Emerging Paradigm

2025-06-01

Mario Siervo , Giuseppe Verdile , Barbora Piknova | Nitric Oxide

Inorganic nitrate plays a crucial role in the regulation of cerebral blood flow and neurotransmission through its conversion to nitric oxide (NO). Astrocytes are star-shaped glial cells and contribute to … Inorganic nitrate plays a crucial role in the regulation of cerebral blood flow and neurotransmission through its conversion to nitric oxide (NO). Astrocytes are star-shaped glial cells and contribute to maintain the blood-brain barrier integrity, regulate neuronal metabolism, support synaptic plasticity and facilitate neurovascular coupling. Inorganic nitrate widely distributed through all organs, with main reservoirs in skeletomuscular and skin tissues. These reserves are easily accessible via bloodstream and processed into nitrite and NO mainly in liver. Processing nitrate/nitrite into NO at organ with main glycogen stores, could suggest an evolutionary coordination between energy metabolism and NO generating pathways. Such spatial arrangement may facilitate the synchronised mobilisation during periods of enhanced metabolic demand, optimising both fuel utilisation and vascular response and assuring optimal fuel distribution. Astrocytes store glycogen in the brain, which support neuronal metabolism during periods of increased neural activity and hypoglycaemia. This review explores the hypothesis that inorganic nitrate may be stored alongside glycogen in astrocytes and serve as critical reserves for NO production in the brain, particularly during hypoxic conditions. We examine the emerging evidence that astrocytes serve as key mediators in this alternative nitrate-nitrite-NO pathway, potentially influencing cerebrovascular regulation, neuronal energetics, and cognitive function. The integration of findings across molecular, cellular, and systems neuroscience offers new perspectives on how inorganic nitrate intake might support brain metabolism and could inform both preventive strategies and therapeutic interventions for neuro-degenerative disorders such as age-related dementia, stroke or Parkinson's Disease.

Explosive discovery, surprising future: The extraordinary journey of nitroglycerin, nitroderivatives and nitric oxide

2025-06-01

Maria Rosa Montinari , Sergio Minelli , John D. Horowitz +1 more | Vascular Pharmacology

CaMKII S-nitrosylation alters post-ischemic recovery of cardiac contractility

2025-06-01

E. Asamudo , A. L. Wilder , Chidera C. Alim +2 more | Journal of Molecular and Cellular Cardiology Plus

Aberrant Protein Nitrosylation Dynamics Underpins Nitrosative Stress in Cardiometabolic Heart Failure with Preserved Ejection Fraction

2025-06-01

Zhen Li , Natalie Gehred , Tatiana Gromova +7 more | Journal of Molecular and Cellular Cardiology Plus

Sustained β-Adrenergic Stress Contributes to Cardiac Hyaluronan Accumulation

2025-06-01

Anand Ramalingam , Caitlin Howard , Kenneth R. Brittian +2 more | Journal of Molecular and Cellular Cardiology Plus

S-nitrosation of CaMKIIα matters, a new mechanism mediating learning and memory

2025-05-30

Boyu Chu , Xinhua Qiao , Chang Chen | Free Radical Biology and Medicine

Inorganic nitrate improves neurovascular and cognitive function in Type 2 diabetic rats

2025-05-30

João S. Gonçalves , Beatriz Nunes , Sandra I. Anjo +3 more | Free Radical Biology and Medicine

Impact of nitro-fatty acids on intracellular nitric oxide level in vitro

2025-05-30

Zdeněk Dostál , Martina Zatloukalová , Barbara Maková +3 more | Free Radical Biology and Medicine

Acetylcholine activates a regenerative vasodilator mechanism that is sensitive to nitric oxide production

2025-05-30

Nelson P. Barrera , Mónica Márquez , Matías Muñoz-Uribe +1 more | Frontiers in Physiology

The conduction of changes in the diameter of arterioles plays an important role in the coordination of the blood flow distribution. The endothelium regulates vasomotor tone by generation of vasodilator … The conduction of changes in the diameter of arterioles plays an important role in the coordination of the blood flow distribution. The endothelium regulates vasomotor tone by generation of vasodilator signals, such as nitric oxide (NO) and endothelium-derived hyperpolarization (EDH). Endothelium-mediated vasodilator responses initiated in an arteriolar segment are conducted along the vessel length, which depends on the electrotonic spread of EDH signaling activated at the stimulation site, but, in contrast, the contribution of NO is controversial. We used the mouse cremaster muscle microcirculation in vivo to analyze the participation of NO in the mechanisms involved in the conducted vasodilation observed in response to the stimulation of a short arteriolar segment with a pulse of acetylcholine (ACh), an endothelium-dependent vasodilator, or S-nitroso-N-acetylpenicillamine (SNAP), an NO donor. The response to ACh spread along the entire vessel showing only a slight decay and, in contrast, the dilation evoked by SNAP was restricted to the stimulation site, independently of the magnitude of the response. Blockade of NO production with 100 μM NG-nitro-L-arginine methyl ester (LNAME) or 100 µM NG-nitro-L-arginine (L-NA) reduced the arteriolar resting diameter by 10%-12%, but the combined application of both blockers enhanced the basal vasoconstrictor tone by ∼38% and inhibited the local (∼45%) and conducted (∼20%-35%) responses initiated by ACh. Interestingly, the conduction of ACh-induced vasodilation increased along the vessel length in the presence of L-NAME and L-NA. In addition, blockade of endothelial cell hyperpolarization exclusively at the stimulation site through microsuperfusion of tetraethylammonium (TEA) inhibited the local vasodilation, but not the conduction of the response. These results suggest that ACh activates an NO sensitive mechanism of regenerative propagation of vasodilator responses, which contributes to our understanding of microvascular function and the complex integration of endothelial signaling pathways in the coordination of the blood flow distribution.

Hydrochlorothiazide

2025-05-30

| Reactions Weekly

Trifolin inhibits the calcium-driven contraction pathway in vascular smooth muscle

2025-05-30

Renfeng Li , Jinkong Wu , Meizhu Wu +7 more | Frontiers in Pharmacology

Trifolin, a bioactive component of the Qingda granule, has demonstrated significant antihypertensive potential; however, its precise mechanisms of action remain largely unknown. This study aimed to investigate the antihypertensive effects … Trifolin, a bioactive component of the Qingda granule, has demonstrated significant antihypertensive potential; however, its precise mechanisms of action remain largely unknown. This study aimed to investigate the antihypertensive effects of trifolin and unravel its underlying molecular mechanisms. The influence of trifolin on vascular contraction and relaxation and its regulatory effects on ion channels were evaluated through a vascular tension experiment. Morphological changes in the aortic tissues of mice with angiotensin Ⅱ-induced hypertension and the expression profiles of contraction-associated proteins were analyzed via hematoxylin-eosin staining and immunohistochemistry. Additionally, trifolin's impact on calcium ion dynamics and contraction-associated protein expression in angiotensin Ⅱ-activated vascular smooth muscle cells (VSMCs) was determined through calcium flux assays and western blot analyses. Trifolin treatment decreased the constriction of isolated abdominal aortic rings induced by norepinephrine, KCl, and angiotensin Ⅱ in an endothelium-independent manner and extracellular Ca2+ influx induced by these three substances and thapsigargin. Moreover, trifolin treatment significantly reduced the abdominal aortic wall thickness and downregulated the expression of store-operated channels channel proteins (STIM1 and ORAI1) and calcium signaling-related proteins (CaM, myosin light chain kinase, and p-MLC2) in the abdominal aorta of hypertensive mice and angiotensin Ⅱ-induced VSMCs. In conclusion, calcium signaling inhibition may underlie trifolin's antihypertensive effects and its ability to ameliorate vascular function. These findings offer new therapeutic insights for hypertension treatment.

Protein nitration in the vascular proteome

2025-05-30

Shuqi Xu , Christine Y. Chuang , Clare L. Hawkins +2 more | Free Radical Biology and Medicine