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Nitric oxide (NO) and hydrogen peroxide (H 2 O 2 ) play key roles in physiological and pathological responses in cardiac myocytes. The mechanisms whereby H 2 O 2 –modulated phosphorylation pathways regulate the endothelial isoform of nitric oxide synthase (eNOS) in these cells are incompletely understood. We show here that H 2 O 2  treatment of adult mouse cardiac myocytes leads to increases in intracellular Ca 2+  ([Ca 2+ ] i ), and document that activity of the L-type Ca 2+  channel is necessary for the H 2 O 2 -promoted increase in sarcomere shortening and of [Ca 2+ ] i . Using the chemical NO sensor Cu 2 (FL2E), we discovered that the H 2 O 2 -promoted increase in cardiac myocyte NO synthesis requires activation of the L-type Ca 2+  channel, as well as phosphorylation of the AMP-activated protein kinase (AMPK), and mitogen-activated protein kinase kinase 1/2 (MEK1/2). Moreover, H 2 O 2 -stimulated phosphorylations of eNOS, AMPK, MEK1/2, and ERK1/2 all depend on both an increase in [Ca 2+ ] i  as well as the activation of protein kinase C (PKC). We also found that H 2 O 2 -promoted cardiac myocyte eNOS translocation from peripheral membranes to internal sites is abrogated by the L-type Ca 2+  channel blocker nifedipine. We have previously shown that kinase Akt is also involved in H 2 O 2 -promoted eNOS phosphorylation. Here we present evidence documenting that H 2 O 2 -promoted Akt phosphorylation is dependent on activation of the L-type Ca 2+  channel, but is independent of PKC. These studies establish key roles for Ca 2+ - and PKC-dependent signaling pathways in the modulation of cardiac myocyte eNOS activation by H 2 O 2 .

Role of Ca2+ in the Control of H2O2-Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes