Role of Ca\(^{2+}\) in the Control of H\(_2\)O\(_2\)-Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes

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Role of Ca\(^{2+}\) in the Control of H\(_2\)O\(_2\)-Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes

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Title: Role of Ca\(^{2+}\) in the Control of H\(_2\)O\(_2\)-Modulated Phosphorylation Pathways Leading to eNOS Activation in Cardiac Myocytes
Author: Shiroto, Takashi; Sartoretto, Simone M.; Pluth, Michael D.; Lippard, Stephen J.; Sartoretto, Juliano Luiz; Kalwa, Hermann H; Michel, Thomas Mark

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Citation: Sartoretto, Juliano L., Hermann Kalwa, Takashi Shiroto, Simone M. Sartoretto, Michael D. Pluth, Stephen J. Lippard, and Thomas Michel. 2012. Role of Ca\(^{2+}\) in the control of H\(_2\)O\(_2\)-modulated phosphorylation pathways leading to eNOS activation in cardiac myocytes. PLoS ONE 7(9): e44627.
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Abstract: 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\(_2\).
Published Version: doi:10.1371/journal.pone.0044627
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435284/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:10589803
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