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Am J Physiol Heart Circ Physiol (February 19, 2004). doi:10.1152/ajpheart.00475.2003
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Submitted on May 22, 2003
Accepted on February 9, 2004

PKC-{epsilon} regulation of extracellular signal-regulated kinase (ERK1/2): A potential role in phenylephrine-induced cardiocyte growth

Vijay U. Rao1, Hirokazu Shiraishi1, and Paul J. McDermott2*

1 Cardiology Division, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA
2 Cardiology Division, Department of Medicine, Medical University of South Carolina, Charleston, SC, USA; Research, Ralph H. Johnson Department of Veterans Affairs Medical Center, Charleston, SC, USA

* To whom correspondence should be addressed. E-mail: mcdermp{at}musc.edu.

Hypertrophic growth of cardiac muscle is dependent on activation of the PKC-{epsilon} isoform. To define the effectors of PKC-{epsilon} involved in growth regulation, recombinant adenoviruses were used to overexpress either wild-type PKC-{epsilon} (PKC-{epsilon}/WT) or dominant-negative PKC-{epsilon} (PKC-{epsilon}/DN) in neonatal rat cardiocytes. PKC-{epsilon}/DN inhibited acute activation of PKC-{epsilon} produced in response to phorbol ester and reduced ERK1/2 activity as measured by phosphorylation of p42 and p44 isoforms. The inhibitory effects were specific to PKC-{epsilon} since PKC-{epsilon}/DN did not prevent translocation of either PKC-{alpha} or PKC-{delta}. Overexpression of PKC-{epsilon}/DN blunted the acute increase in ERK1/2 phorphorylation induced by the {alpha}1-adrenergic agonist phenylephrine (PE ). Inhibition of PKC-{delta} with rottlerin potentiated the effects of PE on ERK1/2 phosphorylation. PKC-{epsilon}/DN adenovirus also blocked cardiocyte growth as measured after 48 h of PE treatment, although the multiplicity of infection was lower than that required to block acute ERK1/2 activation. PE activated p38 MAP kinase as measured by its phosphorylation, but the response was not blocked by PKC inhibitors or by overexpression of PKC-{epsilon}/DN. Taken together, these studies show that the hypertrophic agonist PE regulates ERK1/2 activity in cardiocytes by a pathway dependent on PKC-{epsilon}, and that PE-induced growth is mediated by PKC-{epsilon}.




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[Abstract] [Full Text] [PDF]


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