Superoxide Production and Reactive Oxygen Species Signaling by Endothelial Nitric-oxide Synthase

Wang, Weihan; Wang, Shuibang; Ling, Yan; Madara, Patricia; Cintron, Ana Del Pilar; Wesley, Robert; Danner, Robert L.

doi:10.1074/jbc.m000301200

Cited by 74 publications

(59 citation statements)

References 35 publications

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“…Several proteins produce O 2 Ϫ , including NAD(P)H oxidase (32), xanthine oxidase (33), NO synthase (42), and cyclooxygenase (10). The thick ascending limb expresses all of these, although NAD(P)H oxidase is likely to be a major source of O 2 Ϫ in this segment.…”

Section: No and Omentioning

confidence: 99%

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet

Varela

Herrera

Garvin

2004

American Journal of Physiology-Renal Physiology

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A high-salt diet enhances nitric oxide (NO)-induced inhibition of transport in the thick ascending limb (THAL). Long exposures to NO inhibit Na-K-ATPase in cultured cells. We hypothesized that NO inhibits THAL Na-K-ATPase after long exposures and a high-salt diet would augment this effect. Rats drank either tap water or 1% NaCl for 7-10 days. Na-K-ATPase activity was assessed by measuring ouabain-sensitive ATP hydrolysis by THAL suspensions. After 2 h, spermine NONOate (SPM; 5 M) reduced Na-K-ATPase activity from 0.44 Ϯ 0.03 to 0.30 Ϯ 0.04 nmol P i ⅐ g protein Ϫ1 ⅐ min Ϫ1 in THALs from rats on a normal diet (P Ͻ 0.03). Nitroglycerin also reduced Na-K-ATPase activity (P Ͻ 0.04). After 20 min, SPM had no effect (change Ϫ0.07 Ϯ 0.05 nmol Pi ⅐ g protein Ϫ1 ⅐ min Ϫ1 ). When rats were fed high salt, SPM did not inhibit Na-K-ATPase after 120 min. To investigate whether ONOO Ϫ formed by NO reacting with O 2 Ϫ was involved, we measured O 2 Ϫ production. THALs from rats on normal and high salt produced 35.8 Ϯ 0.3 andϪ production differed, we studied the effects of the O 2 Ϫ scavenger tempol. In the presence of 50 M tempol, SPM did not inhibit Na-K-ATPase after 120 min (0.50 Ϯ 0.05 vs. 0.52 Ϯ 0.07 nmol Pi ⅐ g protein Ϫ1 ⅐ min Ϫ1 ). Propyl gallate, another O 2 Ϫ scavenger, also prevented SPM-induced inhibition of Na-K-ATPase activity. SPM inhibited pump activity in tubules from rats on high salt when O 2 Ϫ levels were increased with xanthine oxidase and hypoxanthine. We concluded that NO inhibits Na-K-ATPase after long exposures when rats are on a normal diet and this inhibition depends on O 2 Ϫ . NO donors do not inhibit Na-K-ATPase in THALs from rats on high salt due to decreased O 2 Ϫ production.superoxide; nitric oxide; Na transport; hypertension NITRIC OXIDE (NO) is an important regulator of renal function, promoting natriuresis and diuresis (9). Intrarenal administration of NO synthesis inhibitors lowers urinary Na excretion (11-13, 17, 19, 20, 22, 38), whereas NO donors induce natriuresis (18,19). NO-induced natriuresis and diuresis can occur in the absence of hemodynamic changes, indicating that NO directly inhibits Na and water absorption along the nephron. In vitro studies have shown that NO blunts transport in isolated proximal tubules (1), cortical collecting ducts (3, 39, 40), inner medullary collecting ducts (2), and thick ascending limbs (2, 34, 35). Additionally, NO has been reported to inhibit Na transport in several cultured renal cells (5,15,16). We reported that the inhibition of net Na absorption caused by NO in the thick ascending limb and cortical collecting duct is due to reduced activity of the transporters responsible for Na entry into the cell, namely, Na/H exchange (4) and Na-K-2Cl cotransport (29) in the thick ascending limb and amiloridesensitive Na channels in the cortical collecting duct (40). We did not find inhibition of basolateral Na-K-ATPase after 20 min of exposure. However, others showed that NO inhibits Na-K-ATPase activity in cultured cells after longer exposures and that inhibition ...

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Section: No and Omentioning

confidence: 99%

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet

Varela

Herrera

Garvin

2004

American Journal of Physiology-Renal Physiology

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“…Importantly, eNOS is a cytochrome P450 reductase-like enzyme that produces superoxide under certain pathological conditions. 19 Vergnani et al 20 reported that oxidized LDL, an atherogenic factor, may uncouple eNOS activity, allowing the enzyme to become a source of superoxide. The interaction between NO and superoxide results in the formation of peroxynitrite, a highly toxic metabolite that can induce tissue damage, suggesting that the scavenging capacity of superoxide by endothelial SOD plays a key role in regulating the production of 2 interrelated but distinct free radicals from eNOS.…”

Section: Fukuo Et Al Nifedipine Indirectly Upregulates Endothelial Sodmentioning

confidence: 99%

Nifedipine Indirectly Upregulates Superoxide Dismutase Expression in Endothelial Cells via Vascular Smooth Muscle Cell–Dependent Pathways

et al. 2002

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Background-Calcium antagonists normalize endothelial dysfunction in many cardiovascular diseases. There is no known receptor, however, for calcium antagonists in endothelial cells (ECs). We hypothesized that vascular smooth muscle cells (VSMCs) are involved in the mechanism underlying the normalization of endothelial dysfunction by calcium antagonists. Methods and Results-Coculture studies with ECs and VSMCs were performed to determine whether VSMCs mediate modulation of endothelial superoxide dismutase (SOD) activity and expression induced by the calcium antagonist nifedipine. Nifedipine induced upregulation of SOD activity in rat aortic segments but had no effect on SOD expression or activity in ECs or VSMCs cultured individually. When ECs were cocultured with VSMCs, however, nifedipine upregulated SOD expression and activity in ECs. Nifedipine stimulated vascular endothelial growth factor (VEGF) production from VSMCs, and this stimulation of VEGF production was abolished by HOE-140, an antagonist of the bradykinin B 2 receptor. A neutralizing antibody against VEGF inhibited the upregulation of endothelial SOD by nifedipine. In addition, recombinant VEGF induced an increase in the levels of SOD expression in ECs, and supernatant derived from nifedipine-treated VSMCs enhanced NO production from ECs. This increase in NO production by the supernatant was inhibited by preincubation of ECs with SOD antisense oligodeoxyribonucleotides. Conclusions-The

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“…Recently, it has become apparent that endothelial nitric oxide synthase (eNOS) can produce large amounts of superoxide under certain pathophysiological conditions. 31,32 One mechanism for this relates to oxidative destruction of tetrahydrobiopterin, which is a critical co-factor for Journal of Human Hypertension eNOS function. [33][34][35] In the absence of tetrahydrobiopterin, eNOS transfers electrons to molecular oxygen rather than to L-arginine, resulting in superoxide production.…”

Section: Receptorsmentioning

confidence: 99%

Central role of the AT1-receptor in atherosclerosis

Nickenig

2002

J Hum Hypertens

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The renin-angiotensin system plays a major role in the pathogenesis of atherosclerosis. Most known effects of angiotensin II are mediated via activation of the AT 1 -receptor, which is in turn influenced to a great degree by levels of expression of the AT 1 -receptor. AT 1 -receptor activation is not only involved in vasoconstriction, water and salt homoeostasis and control of other neurohumoral systems, but also induces reactive oxygen species production, cellular hypertrophy and hyperplasia and apoptosis. Expression of this G-proteincoupled receptor is regulated by multiple factors. Among other conditions, oestrogen deficiency and hypercholesterolaemia increase AT 1 -receptor expression. Experimental data suggest that this augments the actions of angiotensin II, contributes to endothelial dysfunction, increases vascular production of reactive oxygen species, and via these mechanisms Keywords: AT 1 -receptors; atherosclerosis; oxidised LDL; reactive oxygen species; renin-angiotensin system; vascular smooth muscle Angiotensin receptors and cellular functionThe principal effector of the renin angiotensin system, angiotensin II, modulates blood pressure, water and sodium homoeostasis, neuronal function, and other neurohumoral systems.1-3 Initial research with angiotensin II focused on its role in the pathogenesis of hypertension, but in the past decade increasing evidence has accumulated to indicate that this octapeptide is involved in the development of atherosclerosis, myocardial infarction, vascular and myocardial remodelling, and congestive heart failure. [4][5][6][7] The effects of angiotensin II are mediated by two receptors, referred to as the AT 1 -and AT 2 -subtypes. 3,4 In adult tissues, the AT 2 -receptor is predominantly expressed in the brain and adrenals, with lower levels expressed elsewhere.

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Superoxide Production and Reactive Oxygen Species Signaling by Endothelial Nitric-oxide Synthase

Abstract: Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult.

Cited by 74 publications

References 35 publications

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet

Nifedipine Indirectly Upregulates Superoxide Dismutase Expression in Endothelial Cells via Vascular Smooth Muscle Cell–Dependent Pathways

Central role of the AT1-receptor in atherosclerosis

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Superoxide Production and Reactive Oxygen Species Signaling by Endothelial Nitric-oxide Synthase

Abstract: Reactive oxygen species can function as intracellular messengers, but linking these signaling events with specific enzymes has been difficult.

Cited by 74 publications

References 35 publications

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O2−and is diminished by a high-salt diet

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O2−and is diminished by a high-salt diet

Nifedipine Indirectly Upregulates Superoxide Dismutase Expression in Endothelial Cells via Vascular Smooth Muscle Cell–Dependent Pathways

Central role of the AT1-receptor in atherosclerosis

Contact Info

Product

Resources

About

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet

Inhibition of Na-K-ATPase in thick ascending limbs by NO depends on O₂⁻and is diminished by a high-salt diet