Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide

Polte, Tobias; Abate, Aida; Dennery, Phyllis A.; Schröder, H.

doi:10.1161/01.atv.20.5.1209

Cited by 119 publications

(95 citation statements)

References 49 publications

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“…This finding points to the involvement of endogenous NO, an established HO-1-inducing signaling molecule, 12,29,30 as a mediator of L-methioninedependent antioxidant actions. The effects of L-methionine were observed at high micromolar and low millimolar concentrations of L-methionine, which are well within the range of plasma levels after methionine loading.…”

Section: E198mentioning

confidence: 73%

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L-methionine reduces oxidant stress in endothelial cells: Role of heme oxygenase-1, ferritin, and nitric oxide

Erdmann

Grosser

Schröder

2005

AAPS J

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The amino acid L-methionine is known to exert antioxidant effects by as yet unidentified mechanisms. In the present study, L-methionine led to a concentration-dependent induction of the antioxidant proteins heme oxygenase-1 (HO-1) and ferritin in cultured endothelial cells (ECV 304). HO-1 protein expression was accompanied by an increased catalytic activity of the enzyme. Long-term pre-incubation of endothelial cells with L-methionine reduced NADPH-mediated radical formation by up to 60%. The antioxidant effect of L-methionine was mimicked by the HO-1 product bilirubin, which suppressed free radical formation almost completely. Reduction of superoxide generation by L-methionine was inhibited in the presence of the nitric oxide (NO) synthase inhibitor L-NMMA, suggesting the involvement of endogenous NO in L-methionine-dependent cytoprotection. These findings demonstrate that L-methionine reduces free radical formation in endothelial cells, possibly through induction of heme oxygenase-1 and ferritin. This novel, indirect antioxidant action might be relevant for the preventive potential of methionine and methionine rich diets under conditions of inflammation and oxidative stress.

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Section: E198mentioning

confidence: 73%

“…3,12,13 HO-1 is an inducible enzyme that catalyzes the degradation of heme. This process leads to generation of bilirubin, iron, and carbon monoxide (CO).…”

Section: Introductionmentioning

confidence: 99%

L-methionine reduces oxidant stress in endothelial cells: Role of heme oxygenase-1, ferritin, and nitric oxide

Erdmann

Grosser

Schröder

2005

AAPS J

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“…Recently, several studies have suggested a coordinated physiological role for NOS and HO in cytoprotection. 29,30 Thus, it does not seem surprising if CO, a byproduct of heme catabolism by HO, induces NO, which in turn may act to reduce cardiac ischemia-reperfusion injury. But much more investigation may be necessary to clarify the precise relationship between CO and NO.…”

Section: Discussionmentioning

confidence: 99%

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Fujimoto

Ohno

Ayabe

et al. 2004

ATVB

139

120

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Background-Carbon monoxide (CO) is postulated to protect tissues against several types of injuries. We investigated the role of CO in amelioration of cardiac ischemia-reperfusion injury in vivo and the mechanisms involved in it. Methods and Results-Rats inhaled CO (250 ppm, 500 ppm, or 1000 ppm) for 24 hours in a chamber after myocardial ischemia-reperfusion induced by occluding the left anterior descending coronary artery for 30 minutes. Pre-exposure to 1000 ppm of CO significantly reduced the ratio of infarct areas to risk areas and suppressed the migration of macrophages and monocytes into infarct areas, and the expression of tumor necrosis factor (TNF)-␣ in the heart; however, 250 ppm, 500 ppm of CO, or low barometric pressure hypoxia (0.5 atm) did not affect them. Exposure to 1000 ppm CO resulted in the activation of p38 mitogen-activated protein kinase (p38MAPK), protein kinase B␣(Akt), endothelial nitric oxide synthase (eNOS), and cyclic guanosine monophosphate (cGMP) in the myocardium. Inhibition of p38MAPK, PI3kinase, NO, and soluble guanylate cyclase with SB203580, wortmannin, N(G)-nitro-L-arginine methyl ester (L-NAME), and methylene blue, respectively, attenuated the cytoprotection by CO. Conclusion-CO has beneficial effects on cardiac ischemia-reperfusion injury; this effect is mediated by p38MAPK pathway and Akt-eNOS pathway, including production of cGMP.

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“…Thus, NO has been shown to elevate the levels of heme oxygenase-1 mRNA and protein (17)(18)(19)(20)(21)(22)(23)(24)(25), and this response appears to be mediated by a guanylate cyclase-independent mechanism that may subserve a more generalized antioxidant response (18). Conversely, CO has been reported to elevate the steady state level of NO (26), but increased levels of heme oxygenase have been shown to decrease NO concentrations, possibly by consuming the heme required for assembly of the nitric-oxide synthases (27)(28)(29).…”

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confidence: 99%

Interaction of Nitric Oxide with Human Heme Oxygenase-1

Wang¹,

Shen²,

Moënne‐Loccoz³

et al. 2003

Journal of Biological Chemistry

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NO and CO may complement each other as signaling molecules in some physiological situations. We have examined the binding of NO to human heme oxygenase-1 (hHO-1), an enzyme that oxidizes heme to biliverdin, CO, and free iron, to determine whether inhibition of hHO-1 by NO can contribute to the signaling interplay of NO and CO. An Fe 3؉ -NO hHO-1-heme complex is formed with NO or the NO donors NOC9 or 2-(N,N-diethylamino)-diazenolate-2-oxide⅐sodium salt. Resonance Raman spectroscopy shows that ferric hHO-1-heme forms a 6-coordinated, low spin complex with NO. The (N-O) vibration of this complex detected by Fourier transform IR is only 4 cm ؊1 lower than that of the corresponding metmyoglobin (met-Mb) complex but is broader, suggesting a greater degree of ligand conformational freedom. The Fe 3؉ -NO complex of hHO-1 is much more stable than that of met-Mb. Stopped-flow studies indicate that k on for formation of the hHO-1-heme Fe 3؉ -NO complex is ϳ50-times faster, and k off 10 times slower, than for met-Mb, resulting in K d ‫؍‬ 1.4 M for NO. NO thus binds 500-fold more tightly to ferric hHO-1-heme than to met-Mb. The hHO-1 mutations E29A, G139A, D140A, S142A, G143A, G143F, and K179A/R183A do not significantly diminish the tight binding of NO, indicating that NO binding is not highly sensitive to mutations of residues that normally stabilize the distal water ligand. As expected from the K d value, the enzyme is reversibly inhibited upon exposure to pathologically, and possibly physiologically, relevant concentrations of NO. Inhibition of hHO-1 by NO may contribute to the pleiotropic responses to NO and CO. Nitric oxide (NO)1 functions as a signaling molecule in a diversity of physiological responses, including vasodilation and regulation of normal vascular tone, neuronal signal transmission, cytotoxicity against pathogens and tumors, and regulation of cellular respiration (1-3). Most of these responses result from interaction of NO with the heme group of the receptor guanylyl cyclase (1). A role akin to that of NO in signaling pathways has also been postulated for CO (4). CO is produced in mammals from heme by two heme oxygenases, HO-1 and HO-2 (5-8). The involvement of CO has been invoked as a factor in atherosclerosis (9), psoriasis (10), vascular constriction (11), chronic renal inflammation (12), cellular protection (13), hyperoxia-induced lung injury (14), and other physiological situations. The role of CO as an NO-like signaling molecule has received strong support from studies of heme oxygenase and nitric-oxide synthase knockouts (15), but much of the evidence, particularly that which depends heavily on inhibition of heme oxygenase by metalloporphyrins such as tin protoporphyrin IX, is tainted by ambiguities concerning the specificity of the inhibitors (16). Nevertheless, the collective evidence makes a persuasive case for at least a limited role for CO in mammalian signaling systems.Evidence has accumulated that interactions of CO and NO may influence the physiological responses to each of these agents thr...

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Heme Oxygenase-1 Is a cGMP-Inducible Endothelial Protein and Mediates the Cytoprotective Action of Nitric Oxide

Cited by 119 publications

References 49 publications

L-methionine reduces oxidant stress in endothelial cells: Role of heme oxygenase-1, ferritin, and nitric oxide

L-methionine reduces oxidant stress in endothelial cells: Role of heme oxygenase-1, ferritin, and nitric oxide

Carbon Monoxide Protects Against Cardiac Ischemia—Reperfusion Injury In Vivo via MAPK and Akt—eNOS Pathways

Interaction of Nitric Oxide with Human Heme Oxygenase-1

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