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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis
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Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

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Nitric oxide (NO) and hydrogen peroxide (H_2O_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(FL2E) to study adult cardiac myocytes from wild-type, eNOS_(null), and nNOS_(null) mice, we discovered that physiological concentrations of H_2O_2 activate eNOS but not nNOS. H_2O_2-stimulated eNOS activation depends on phosphorylation of both the AMP-activated 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_2O_2biosensor HyPer2 show marked H _2O_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_2O_2, whereas β- adrenergic contractile responses occur independently of H_2O_2 signaling. These studies establish differential roles for H_2O_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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