CELL-TYPE-SPECIFIC ANGIOTENSIN II-EVOKED SIGNAL-TRANSDUCTION PATHWAYS- CRITICAL ROLES OF G(BETA-GAMMA) SUBUNIT, SRC FAMILY, AND RAS IN CARDIAC FIBROBLASTS

Angiotensin II (Ang II) induces hypertrophy of cardiac myocytes and hy perplasia of cardiac fibroblasts. To determine the molecular mechanism by which Ang II displayed different effects on cardiac myocytes and f ibroblasts, we examined signal transduction pathways leading to activa tion of extracellular signal-regulated kinases (ERKs). Ang II-induced ERK activation was abolished by pretreatment with pertussis toxin and by overexpression of the G(beta gamma) subunit-binding domain of the b eta-adrenergic receptor kinase 1 in cardiac fibroblasts but not in car diac myocytes. Inhibition of protein kinase C strongly inhibited activ ation of ERKs by Ang II in cardiac myocytes, whereas inhibitors of tyr osine kinases but not of protein kinase C abolished Ang II-induced ERK activation in cardiac fibroblasts, Overexpression of C-terminal Src k inase (Csk), which inactivates Src family tyrosine kinases, suppressed the activation of transfected ERK in cardiac fibroblasts. Ang II rapi dly induced phosphorylation of Shc and association of Shc with Grb2. C otransfection of the dominant-negative mutant of Ras or Raf-1 kinase a bolished Ang II-induced ERK activation in cardiac fibroblasts. Overexp ression of Csk or the dominant-negative mutant of Ras had no effects o n Ang II-induced ERK activation in cardiac myocytes. These findings su ggest that Ang II-evoked signal transduction pathways differ among cel l types, In cardiac fibroblasts, Ang II activates ERKs through a pathw ay including the G(beta gamma) subunit of G(i) protein, tyrosine kinas es including Src family tyrosine kinases, Shc, Grb2, Ras, and Raf-1 ki nase, whereas G(q) and protein kinase C are important in cardiac myocy tes.