l-Arginine Chlorination Products Inhibit Endothelial Nitric Oxide Production

Zhang, Chunxiang; Reiter, Chris; Eiserich, Jason P.; Boersma, Brenda J.; Parks, Dale A.; Beckman, Joseph S.; Barnes, Stephen; Kirk, Marion; Baldus, Stephan; Darley‐Usmar, Victor; White, C. Roger

doi:10.1074/jbc.m100191200

Cited by 78 publications

(70 citation statements)

References 34 publications

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“…Previous studies have shown that Cav-1 can bind and negatively regulate eNOS activity (27,45,46). To determine whether the loss of cav-1͞caveolae could lead to a high NO levels, we assayed the systemic NO levels in littermates of cav-1 Ϫ/Ϫ and wild-type mice (47). In the plasma prepared from the cav-1 Ϫ/Ϫ mice, the NO concentration was about 5-fold higher than that in the wild-type mice (1.73 Ϯ 0.37 M in cav-1 ϩ/ϩ mice, n ϭ 12; vs. 9.7 Ϯ 2.3 M in cav-1 Ϫ/Ϫ mice, n ϭ 12, P Ͻ 0.01).…”

Section: Cav-1 Deficiency Causes Pulmonary Hypertension and Resultingmentioning

confidence: 99%

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Zhao

Liu

Stan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

432

382

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Caveolins are important components of caveolae, which have been implicated in vesicular trafficking and signal transduction. To investigate the in vivo significance of Caveolins in mammals, we generated mice deficient in the caveolin-1 (cav-1) gene and have shown that, in the absence of Cav-1, no caveolae structures were observed in several nonmuscle cell types. Although cav-1 ؊/؊ mice are viable, histological examination and echocardiography identified a spectrum of characteristics of dilated cardiomyopathy in the left ventricular chamber of the cav-1-deficient hearts, including an enlarged ventricular chamber diameter, thin posterior wall, and decreased contractility. These animals also have marked right ventricular hypertrophy, suggesting a chronic increase in pulmonary artery pressure. Direct measurement of pulmonary artery pressure and histological analysis revealed that the cav-1 ؊/؊ mice exhibit pulmonary hypertension, which may contribute to the right ventricle hypertrophy. In addition, the loss of Cav-1 leads to a dramatic increase in systemic NO levels. Our studies provided in vivo evidence that cav-1 is essential for the control of systemic NO levels and normal cardiopulmonary function.

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Section: Cav-1 Deficiency Causes Pulmonary Hypertension and Resultingmentioning

confidence: 99%

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Zhao

Liu

Stan

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

432

382

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“…Notably, peroxynitrite formed from superoxide anion radical and ⅐ NO decreases ⅐ NO availability and damages endothelial nitric-oxide synthase directly (5) or indirectly (49). Similarly, HOCl effectively decreases L-arginine availability (15) and enhances superoxide anion radical produc- tion via endothelial nitric-oxide synthase uncoupling (16). Therefore, the ability of probucol and DTBP to attenuate HOCl-induced endothelial dysfunction may result from decreased vascular superoxide anion radical production, as suggested previously for probucol (27), or from oxidant scavenging.…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence that HOCl-mediated oxidation occurs within and outside endothelial cells of human atherosclerotic lesions, based on immunostaining with a monoclonal antibody specific for HOCl-modified proteins (13). Also, HOCl-modified low density lipoprotein, present in human lesions (13), can inhibit ⅐ NO production by endothelial cells (14), and HOClmediated chlorination of L-arginine can produce a similar defect in endothelial cell ⅐ NO synthesis (15). Furthermore, HOCl impairs endothelial function by decreasing the stability of endothelial nitric-oxide synthase (16).…”

mentioning

confidence: 99%

Probucol Protects against Hypochlorite-induced Endothelial Dysfunction

Witting

Raftery

et al. 2005

Journal of Biological Chemistry

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Atherosclerosis is associated with endothelial dysfunction and a heightened state of inflammation characterized, in part, by an increase in vascular myeloperoxidase and proteins modified by its principal oxidant, hypochlorous acid (HOCl). Here we examined whether probucol could protect against endothelial dysfunction induced by the two-electron oxidant HOCl. Hypochlorous acid eliminated endothelium-dependent relaxation of rabbit aorta, whereas endothelial function and tissue cGMP was preserved and elevated, respectively, in animals pretreated with probucol. Exogenously added probucol also protected against HOClinduced endothelial dysfunction. In vitro, HOCl oxidized probucol in a two-phase process with rate constants k 1 ‫؍‬ 2.7 ؎ 0.3 ؋ 10 2 and k 2 ‫؍‬ 0.7 ؎ 0.2 ؋ 10 2 M ؊1 s ؊1 that resulted in a dose-and time-dependent accumulation of probucolderived disulfoxide, 4,4-dithiobis(2,6-di-tert-butyl-phenol) (DTBP), DTBP-derived thiosulfonate, disulfone, and sulfonic acid, together with 3,3,5,5-tetra-tert-butyl-4,4-diphenoquinone (DPQ) as determined by high performance liquid chromatography and mass spectrometry. Like HOCl, selected one-electron oxidants converted probucol into DTBP and DPQ. Also, dietary and in vitro added DTBP protected aortic rings from HOCl-induced endothelial dysfunction and in vitro oxidation by HOCl gave rise to the thiosulfonate, disulfone, and sulfonic acid intermediates and DPQ. However, the product profiles of the in vitro oxidation systems were different from those in aortas of rabbits receiving dietary probucol or DTBP ؎ HOCl treatment. Together, the results show that both probucol and DTBP react with HOCl and protect against HOClinduced endothelial dysfunction, although direct scavenging of HOCl is unlikely to be responsible for the vascular protection by the two compounds.

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“…• NO formation/bioavailability in several ways: (i) HOCl can chlorinate arginine, the substrate of eNOS, thereby limiting arginine bioavailability and forming chlorinated arginine that can also directly inhibit eNOS [81]; (ii) HOCl can directly oxidize eNOS, leading to monomerization and uncoupling of the synthase [59]; and (iii) lipoproteins modified in vitro by the MPO/H 2 O 2 /NO 2 − system may cause dissociation of eNOS from the plasma membrane of endothelial cells and decrease eNOS expression [82].…”

Section: Promotion Of Endothelial Dysfunctionmentioning

confidence: 99%

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

et al. 2016

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Atherosclerosis is the main pathophysiological process underlying coronary artery disease (CAD). Acute complications of atherosclerosis, such as myocardial infarction, are caused by the rupture of vulnerable atherosclerotic plaques, which are characterized by thin, highly inflamed, and collagen-poor fibrous caps. Several lines of evidence mechanistically link the heme peroxidase myeloperoxidase (MPO), inflammation as well as acute and chronic manifestations of atherosclerosis. MPO and MPO-derived oxidants have been shown to contribute to the formation of foam cells, endothelial dysfunction and apoptosis, the activation of latent matrix metalloproteinases, and the expression of tissue factor that can promote the development of vulnerable plaque. As such, detection, quantification and imaging of MPO mass and activity have become useful in cardiac risk stratification, both for disease assessment and in the identification of patients at risk of plaque rupture. This review summarizes the current knowledge about the role of MPO in CAD with a focus on its possible roles in plaque rupture and recent advances to quantify and image MPO in plasma and atherosclerotic plaques.

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l-Arginine Chlorination Products Inhibit Endothelial Nitric Oxide Production

Cited by 78 publications

References 34 publications

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Defects in caveolin-1 cause dilated cardiomyopathy and pulmonary hypertension in knockout mice

Probucol Protects against Hypochlorite-induced Endothelial Dysfunction

The roles of myeloperoxidase in coronary artery disease and its potential implication in plaque rupture

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