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(Hypertension. 2008;51:704.)
© 2008 American Heart Association, Inc.

Original Articles

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

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.

Correspondence to J. Gary Meszaros, Northeastern Ohio Universities College of Medicine, Department of Physiology and Pharmacology, 4209 State Rt 44, Rootstown, OH 44272-0095. E-mail jgmeszar{at}neoucom.edu

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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