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Hydrogen peroxide differentially modulates cardiac myocyte nitric oxide synthesis

Nitric oxide (NO) and hydrogen peroxide (H2O2) 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 [Cu2(FL2E)] to study adult cardiac myocytes from wild-type, eNOSnull, and nNOSnull mice, we discovered that physiological concentrations of H2O2 activate eNOS but not nNOS. H2O2-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 H2O2 biosensor HyPer2 show marked H2O2 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 H2O2, whereas β-adrenergic contractile responses occur independently of H2O2 signaling. These studies establish differential roles for H2O2 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.