CA2-GROWTH COUPLING IN ANGIOTENSIN-II-INDUCED HYPERTROPHY IN CULTUREDRAT CARDIAC-CELLS()

Objectives: There remain some controversies about the effect of angiot ensin II on intracellular Ca2+ concentration ([Ca2+](i)) in cardiac my ocytes. The aim of this study was to investigate different roles of in tracellular Ca2+ in the responses to angiotensin II between cardiac my ocytes and nonmyocytes. Methods: Primary cultures of neonatal rat card iac myocytes and nonmyocytes were prepared. [Ca2+](i) was measured wit h indo-1. Cellular growth was assayed by [H-3]thymidine uptake, RNA co ntent, [H-3]phenylalanine incorporation and protein content. Induction of immediate-early gene was examined by Northern blot analysis. Resul ts: In myocytes, angiotensin II decreased [Ca2+](i) transients, induce d c-fos mRNA, and accelerated hypertrophy. These effects were complete ly suppressed by AT(1) receptor blockade or protein kinase C inhibitio n. After chelation of extracellular Ca2+, angiotensin II caused no cha nge in [Ca2+](i) or no induction of c-fos in myocytes. Phorbol 12-myri state 13-acetate also decreased [Ca2+](i) transients, caused c-fos ind uction, and provoked hypertrophy in myocytes. In nonmyocytes, angioten sin II increased [Ca2+](i) transiently, induced c-fos mRNA and hypertr ophy. These effects of angiotensin II were not fully abolished by prot ein kinase C inhibition. Extracellular Ca2+ chelation did not complete ly inhibit the effects of angiotensin II on [Ca2+](i) or c-fos inducti on in nonmyocytes. Phorbol 12-myristate 13-acetate did not affect [Ca2 +](i) or cellular growth in nonmyocytes but did cause c-fos induction. Conclusions: These results suggest that angiotensin II induces cellul ar hypertrophy and immediate-early genes through the activation of pro tein kinase C in myocytes, although angiotensin II decreases [Ca2+](i) transients via this signaling pathway. Induction by angiotensin II of hypertrophy and immediate-early genes in nonmyocytes may be in part m ediated by a transient increase in [Ca2+](i) which acts synergisticall y with protein kinase C activation.