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

Jin, Benjamin Y.; Sartoretto, Juliano L.; Gladyshev, Vadim N.; Michel, Thomas

doi:10.1073/pnas.0907409106

Cited by 39 publications

(30 citation statements)

References 46 publications

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“…42 H 2 O 2 could activate endothelial AMPK through Ca 2+ / CaM-dependent protein kinase β pathway within its physiological concentrations, which could be a possible important feedback mediator of AMPK. 43 In the present study, we found that vascular smooth muscle cell hyperpolarization of mesenteric arteries (in the presence of NO and prostacyclin inhibitors) was significantly impaired in eAMPK-KO mice with reduced relaxation responses, indicating that eAMPK is substantially involved in EDH responses. …”

Section: Endothelial Ampk Mediates Edhmentioning

confidence: 53%

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Enkhjargal

Godo

Sawada

et al. 2014

ATVB

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Objective— Vascular endothelium plays an important role to maintain cardiovascular homeostasis through several mechanisms, including endothelium-dependent hyperpolarization (EDH). We have recently demonstrated that EDH is involved in endothelial metabolic regulation in mice. However, it remains to be examined whether AMP-activated protein kinase (AMPK), an important metabolic regulator, is involved in EDH and if so, whether endothelial AMPK (eAMPK) plays a role for circulatory regulation. Approach and Results— We examined the role of eAMPK in EDH, using mice with endothelium-specific deficiency of α-catalytic subunit of AMPK, either α 1 (eAMPKα 1 −/− α 2 +/+ ) or α 2 (eAMPKα 1 +/+ α 2 −/− ) alone or both of them (eAMPKα 1 −/− α 2 −/− ). We performed telemetry, organ chamber, electrophysiological, and Langendorff experiments to examine blood pressure, vascular responses, hyperpolarization of membrane potential, and coronary flow responses, respectively. Hypertension was noted throughout the day in eAMPKα 1 −/− α 2 −/− and eAMPKα 1 −/− α 2 +/+ but not in eAMPKα 1 +/+ α 2 −/− mice when compared with respective control. Importantly, endothelium-dependent relaxations, EDH, and coronary flow increase were all significantly reduced in eAMPKα 1 −/− α 2 −/− and eAMPKα 1 −/− α 2 +/+ but not in eAMPKα 1 +/+ α 2 −/− mice. In contrast, endothelium-independent relaxations to sodium nitroprusside (a NO donor), NS-1619 (a Ca 2+ -activated K + channel opener), and exogenous H 2 O 2 were almost comparable among the groups. In eAMPKα 1 −/− α 2 −/− mice, antihypertensive treatment with hydralazine or long-term treatment with metformin (a stimulator of AMPK) failed to restore EDH-mediated responses. Conclusions— These results provide the first direct evidence that α 1 subunit of eAMPK substantially mediates EDH responses of microvessels and regulates blood pressure and coronary flow responses in mice in vivo, demonstrating the novel role of eAMPK in cardiovascular homeostasis.

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Section: Endothelial Ampk Mediates Edhmentioning

confidence: 53%

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Enkhjargal

Godo

Sawada

et al. 2014

ATVB

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“…The HyPer2 H 2 O 2 biosensor yields an increase in fluorescence that is highly specific for H 2 O 2 . This biosensor has been characterized extensively in vitro and in cultured cells (29,(31)(32)(33). We isolated cardiac myocytes from mice after tail vein injection with the HyPer2 lentivirus and analyzed changes in cell-derived fluorescence after treating the cells with H 2 O 2 , Ang-II, or isoproterenol (Fig.…”

Section: Resultsmentioning

confidence: 99%

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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“…Studies using the H2O2 biosensor, HyPer, 103 showed that eNOS knockdown led to increased H2O2 and AMPK phosphorylation in endothelial cells. 101 Clearly, there is a close interplay between physiological levels of H2O2 and eNOS-dependent signaling pathways (Figure 7). Higher H2O2 concentrations appear to have broader effects on oxidant-modulated signaling pathways.…”

Section: Akt-and Ampk-dependent Enos Phosphorylationmentioning

confidence: 99%

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

Maron

Michel

2012

Circ J

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Reactive oxygen species (ROS) have long been viewed as deleterious chemicals that lead to oxidative stress. More recently, ROS, especially the stable ROS hydrogen peroxide (H2O2), have been shown to have roles in normal physiological responses in vascular cells. Endothelial nitric oxide synthase (eNOS) is dynamically targeted to plasmalemmal caveolae, and represents the principal enzymatic source of nitric oxide (NO • ) in the vascular wall. eNOS maintains normal vascular tone and inhibits the clinical expression of many cardiovascular diseases. Increases in oxidative stress are associated with eNOS dysfunction. In a paradigm shift in the conceptual framework linking redox biochemistry and vascular function, H2O2 has been established as a physiological mediator in signaling pathways, yet the intracellular sources of H2O2 and their regulation remain incompletely understood. The subcellular distributions of ROS and of ROS-modified proteins critically influence the redox-sensitive regulation of eNOS-dependent pathways. ROS localization in specific subcellular compartments can lead to selective oxidative modifications of eNOS and eNOS-associated proteins. Likewise, the dynamic targeting of eNOS and other signaling proteins influences their interactions with reactive nitrogen species and ROS that are also differentially distributed within the cell. Thus, the subcellular distribution both of eNOS and redox-active biomolecules serves as a critical basis for the control of the "redox switch" that influences NO• - and oxidant-regulated signaling pathways. Here we discuss the biochemical factors, cellular determinants, and molecular mechanisms that modulate redox-sensitive regulation of eNOS and NO tion of eNOS is dynamically regulated 9 and the enzyme is thus exposed to different concentrations of ROS depending upon where in the cell the protein is localized. Alterations in eNOS function due to changes in ROS levels may reflect either physiological or pathological responses in both normal cells and in vascular disease states. The relationship between impaired eNOS activity and the development of vascular dysfunction has been extensively studied: NO • is a potent vasodilator molecule that also attenuates platelet aggregation, vascular smooth muscle cell (VSMC) proliferation, and negative vascular remodeling. 10 Collectively, these properties contribute to the prevention of intermediate pathophenotypes of vascular disease, including cardiac and/or vascular hypertrophy, fibrosis, and atherosclerosis. In counterpoise to these deleterious effects of ROS, there also appears to be a key physiological role for H2O2 in eNOS regulation. 11 Elucidating the redoxdependent mechanisms involved in the physiological and pathophysiological regulation of eNOS by ROS will provide critical new insights into vascular disease states and may lead to the identification of novel treatment targets related to eNOS and eNOS-modulated vascular responses.

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

Abstract: mice; pooled data are also shown. * , P Ͻ 0.05; , P Ͻ 0.01; * , P Ͻ 0.001.

Cited by 39 publications

References 46 publications

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

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

Abstract: mice; pooled data are also shown. * , P Ͻ 0.05; ** , P Ͻ 0.01; *** , P Ͻ 0.001.

Cited by 39 publications

References 46 publications

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Endothelial AMP-Activated Protein Kinase Regulates Blood Pressure and Coronary Flow Responses Through Hyperpolarization Mechanism in Mice

Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Subcellular Localization of Oxidants and Redox Modulation of Endothelial Nitric Oxide Synthase

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Abstract: mice; pooled data are also shown. * , P Ͻ 0.05; , P Ͻ 0.01; * , P Ͻ 0.001.