Published Online
on January 14, 2008

A more recent version of this article appeared on March 1, 2008

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Submitted on July 23, 2007
Revised on August 17, 2007

Angiotensin II–Induced Extracellular Signal–Regulated Kinase 1/2 Activation Is Mediated by Protein Kinase C and Intracellular Calcium in Adult Rat Cardiac Fibroblasts

Erik R. Olson; Patricia E. Shamhart; Jennifer E. Naugle; and J. Gary Meszaros^*

From the Department of Physiology and Pharmacology, Northeastern Ohio Universities College of Medicine, Rootstown; and the Graduate Program, School of Biomedical Sciences, Kent State University, Kent, Ohio.

^* To whom correspondence should be addressed. E-mail: jgmeszar{at}neoucom.edu.

Abstract—Angiotensin II (Ang II)–induced proliferation of cardiac fibroblasts is a major contributing factor to the pathogenesis of cardiac fibrosis. Ang II activates extracellular signal–regulated kinase (ERK) 1/2 to induce cardiac fibroblast proliferation, but the signaling pathways leading to ERK 1/2 activation have not been elucidated in these cells. The goal of the current study was to identify the intracellular mediators of Ang II–induced ERK 1/2 activation in adult rat cardiac fibroblasts. We determined that 100 nmol/L of Ang II–induced ERK 1/2 phosphorylation is inhibited by simultaneous chelation of cytosolic calcium and downregulation of protein kinase C (PKC) by phorbol ester or by the specific PKC inhibitor rottlerin, as well as PKC small interfering RNA, but not by inhibition of 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetate, phorbol ester, rottlerin, or PKC small interfering RNA alone. We also found that Ang II does not transactivate the epidermal growth factor receptor in adult cardiac fibroblasts, because pretreatment with 1 µmol/L of AG 1478 did not significantly inhibit [³H]-thymidine incorporation or ERK 1/2 activation. In addition, immunoprecipitation of the epidermal growth factor receptor demonstrated no significant Ang II–induced phosphorylation of tyrosine residues. Inhibition of phosphatidylinositide 3-kinase, PKC, and src tyrosine kinase had no effect on Ang II–induced ERK 1/2 activation. Collectively, these data demonstrate that Ang II does not transactivate the epidermal growth factor receptor in adult rat cardiac fibroblasts to activate ERK 1/2, a common pathway described in vascular smooth muscle and other cell types, but rather occurs via activation of distinct parallel signaling pathways mechanistically controlled by intracellular Ca²⁺ and PKC.

Key words: cellular proliferation • mitogen-activated protein kinase • transactivation • heart failure • fibrosis

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