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Role of Ca[superscript 2+] in the Control of H[subscript 2]O[subscript 2-]Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes

Author(s)
Sartoretto, Juliano L.; Kalwa, Hermann; Shiroto, Takashi; Sartoretto, Simone M.; Pluth, Michael D.; Lippard, Stephen J.; Michel, Thomas; ... Show more Show less
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Abstract
Nitric oxide (NO) and hydrogen peroxide (H[subscript 2]O[subscript 2]) play key roles in physiological and pathological responses in cardiac myocytes. The mechanisms whereby H[subscript 2]O[subscript 2]–modulated phosphorylation pathways regulate the endothelial isoform of nitric oxide synthase (eNOS) in these cells are incompletely understood. We show here that H[subscript 2]O[subscript 2] treatment of adult mouse cardiac myocytes leads to increases in intracellular Ca[superscript 2+] ([Ca[superscript 2+]][superscript i]), and document that activity of the L-type Ca[superscript 2+] channel is necessary for the H2O2-promoted increase in sarcomere shortening and of [Ca[superscript 2+]][superscript i]. Using the chemical NO sensor Cu[subscript 2](FL2E), we discovered that the H[subscript 2]O[subscript 2]-promoted increase in cardiac myocyte NO synthesis requires activation of the L-type Ca[superscript 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[subscript 2]O[subscript 2]-stimulated phosphorylations of eNOS, AMPK, MEK1/2, and ERK1/2 all depend on both an increase in [Ca[superscript 2+]]i as well as the activation of protein kinase C (PKC). We also found that H[subscript 2]O[subscript 2]-promoted cardiac myocyte eNOS translocation from peripheral membranes to internal sites is abrogated by the L-type Ca[superscript 2+] channel blocker nifedipine. We have previously shown that kinase Akt is also involved in H[subscript 2]O[subscript 2]-promoted eNOS phosphorylation. Here we present evidence documenting that H[subscript 2]O[subscript 2]-promoted Akt phosphorylation is dependent on activation of the L-type Ca[superscript 2+] channel, but is independent of PKC. These studies establish key roles for Ca[superscript 2+]- and PKC-dependent signaling pathways in the modulation of cardiac myocyte eNOS activation by H[subscript 2]O[subscript 2].
Date issued
2012-09
URI
http://hdl.handle.net/1721.1/76653
Department
Massachusetts Institute of Technology. Department of Chemistry
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Sartoretto, Juliano L. et al. “Role of Ca[superscript 2+] in the Control of H[subscript 2]O[subscript 2-]Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes.” Ed. Gianfranco Pintus. PLoS ONE 7.9 (2012): e44627.
Version: Final published version
ISSN
1932-6203

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