Cell Type–Specific Angiotensin II–Evoked Signal Transduction Pathways

Critical Roles of G_ß Subunit, Src Family, and Ras in Cardiac Fibroblasts

From the Department of Medicine III (Y.Z., I.K., T.Y., S.K., R.A., W.Z., I.S., Y.H., K.T., T.K., Y.Y.), University of Tokyo School of Medicine, and the Health Service Center (T.Y.), University of Tokyo (Japan).

Correspondence to Issei Komuro, MD, PhD, Department of Medicine III, University of Tokyo School of Medicine, 7–3-1 Hongo, Bunkyo-ku, Tokyo 113, Japan. E-mail komuro-tky{at}umin.u-tokyo.ac.jp

Abstract—Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and fibroblasts, we examined signal transduction pathways leading to activation of extracellular signal–regulated kinases (ERKs). Ang II–induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the G_ß subunit–binding domain of the ß-adrenergic receptor kinase 1 in cardiac fibroblasts but not in cardiac myocytes. Inhibition of protein kinase C strongly inhibited activation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyrosine kinases but not of protein kinase C abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of C-terminal Src kinase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapidly induced phosphorylation of Shc and association of Shc with Grb2. Cotransfection of the dominant-negative mutant of Ras or Raf-1 kinase abolished Ang II–induced ERK activation in cardiac fibroblasts. Overexpression of Csk or the dominant-negative mutant of Ras had no effects on Ang II–induced ERK activation in cardiac myocytes. These findings suggest that Ang II–evoked signal transduction pathways differ among cell types. In cardiac fibroblasts, Ang II activates ERKs through a pathway including the G_ß subunit of G_i protein, tyrosine kinases including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 kinase, whereas G_q and protein kinase C are important in cardiac myocytes.

Key Words: angiotensin II • cardiac fibroblast • extracellular signal–regulated kinase • G protein • Src

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