The Regulation and Pharmacology of Endothelial Nitric Oxide Synthase

Dudzinski, David M.; Igarashi, Jun–ichi; Greif, Daniel M.; Michel, Thomas

doi:10.1146/annurev.pharmtox.44.101802.121844

Cited by 358 publications

(346 citation statements)

References 227 publications

(218 reference statements)

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“…We found that H 2 O 2 treatment increases myocyte eNOS phosphorylation on serine residues 1177 and 633 ( Fig. 1 B and C), sites associated with eNOS enzyme activation (11). The increase in eNOS phosphorylation at these sites occurs at concentrations of added H 2 O 2 that are within the physiological range (4).…”

Section: Resultsmentioning

confidence: 70%

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Sartoretto

Kalwa

Pluth

et al. 2011

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

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Nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ) are synthesized within cardiac myocytes and play key roles in modulating cardiovascular signaling. Cardiac myocytes contain both the endothelial (eNOS) and neuronal (nNOS) NO synthases, but the differential roles of these NOS isoforms and the interplay of reactive oxygen species and reactive nitrogen species in cardiac signaling pathways are poorly understood. Using a recently developed NO chemical sensor [Cu 2 ðFL2EÞ] to study adult cardiac myocytes from wild-type, eNOS null , and nNOS null mice, we discovered that physiological concentrations of H 2 O 2 activate eNOS but not nNOS. H 2 O 2 -stimulated eNOS activation depends on phosphorylation of both the AMPactivated protein kinase and kinase Akt, and leads to the robust phosphorylation of eNOS. Cardiac myocytes isolated from mice infected with lentivirus expressing the recently developed H 2 O 2 biosensor HyPer2 show marked H 2 O 2 synthesis when stimulated by angiotensin II, but not following β-adrenergic receptor activation. We discovered that the angiotensin-II-promoted increase in cardiac myocyte contractility is dependent on H 2 O 2 , whereas β-adrenergic contractile responses occur independently of H 2 O 2 signaling. These studies establish differential roles for H 2 O 2 in control of cardiac contractility and receptor-dependent NOS activation in the heart, and they identify new points for modulation of NO signaling responses by oxidant stress.

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Section: Resultsmentioning

confidence: 70%

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Sartoretto

Kalwa

Pluth

et al. 2011

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

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“…eNOS is a Ca 2ϩ /calmodulin-dependent enzyme that is regulated by phosphorylation at multiple residues (23,36). AMPK is one of several kinases that stimulate eNOS phosphorylation (17,20,37).…”

Section: Discussionmentioning

confidence: 99%

Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells

Jin

Sartoretto

Gladyshev

et al. 2009

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

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“…While we focus on eNOS regulation by S1P receptor systems in this article, readers are invited to another review paper in which we discussed more general aspects of the eNOS/NO system. 21 3.2 Endothelial sphingosine-1-phosphate receptors that activate endothelial nitric oxide synthase…”

Section: Cellular Sources Of Blood Sphingosine-1-phosphate That Modulmentioning

confidence: 99%

“…eNOS phosphorylation pathways also involve other protein kinases and phosphatases at additional serine/threonine and tyrosine residues. 21,58 4. Sphingosine-1-phosphate as a constricting agent of vascular smooth muscle cells…”

Section: Endothelial Signalling Machinery That Connects Sphingosine-1mentioning

confidence: 99%

Sphingosine-1-phosphate and modulation of vascular tone

Igarashi¹,

Michel²

2009

Cardiovascular Research

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Sphingosine-1-phosphate (S1P) is a phosphorylated product of sphingosine, the core structure of the class of lipids termed sphingolipids. S1P is a naturally occurring lipid metabolite, and usually is present at a concentration of a few 100 nanomolar in human sera. S1P has been found to exert a diverse set of physiological and pathophysiological responses in mammalian tissues through the activation of heterotrimeric G-proteins that in turn modulate the activity of various downstream effecter molecules. In blood vessels, vascular endothelial cells and smooth muscle cells express specific receptors for S1P that modulate vascular tone. This article will provide a brief overview of S1P metabolism in the vasculature and will discuss some of the pathways whereby S1P regulates intracellular signal transduction pathways in endothelial and smooth muscle cells, leading to the activation of both vasorelaxation and vasoconstriction responses.

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The Regulation and Pharmacology of Endothelial Nitric Oxide Synthase

Cited by 358 publications

References 227 publications

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Endothelial nitric oxide synthase negatively regulates hydrogen peroxide-stimulated AMP-activated protein kinase in endothelial cells

Sphingosine-1-phosphate and modulation of vascular tone

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