deltaPKC inhibition or varepsilonPKC activation repairs endothelial vascular dysfunction by regulating eNOS post-translational modification.

The balance between endothelial nitric oxide synthase (eNOS)-derived nitric oxide (NO) and reactive oxygen species production determines endothelial-mediated vascular homeostasis. Activation of protein kinase C has been linked to imbalance of the system, which leads to endothelial dysfunction. We previously found that selective inhibition of delta or selective activation of epsilon duanyu1531 reduces oxidative damage in the heart following myocardial infarction. In this study we determined the effect of these duanyu1531 isozymes in the survival of coronary endothelial cells (CVEC). We demonstrate here that serum deprivation of CVEC increased eNOS-mediated levels, activated caspase-3, reduced Akt phosphorylation and cell number. Treatment with either the inhibitor, deltaV1-1, or the activator, psivarepsilonRACK, inhibited these effects, restoring cell survival through inhibition of eNOS activity. The decrease in eNOS activity coincided with specific de-phosphorylation of eNOS at Ser1179, and eNOS phosphorylation at Thr497 and Ser116. Furthermore, deltaV1-1 or psivarepsilonRACK induced physical association of eNOS with caveolin-1, an additional marker of eNOS inhibition, and restored Akt activation by inhibiting its nitration. Together our data demonstrate that (1) in endothelial dysfunction, duanyu1670 and reactive nitrogen species formation result from uncontrolled eNOS activity mediated by activation of deltaduanyu1531 or inhibition of (2) inhibition of deltaduanyu1531 or activation of varepsilonduanyu1531 corrects the perturbed phosphorylation state of eNOS, thus increasing cell survival. Since endothelial health ensures better tissue perfusion and oxygenation, treatment with a deltaduanyu1531 inhibitor and/or an varepsilonduanyu1531 activator in diseases of endothelial dysfunction should be considered. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

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