CA2+-GROWTH COUPLING IN ANGIOTENSIN-II-INDUCED HYPERTROPHY IN CULTURED RAT CARDIAC-CELLS

Objectives: There remain some controversies about the effect of angiotensin II on intracellular Ca2+ concentration ([Ca2+](i)) in cardiac myocytes. The aim of this study was to investigate different roles of intracellular Ca2+ in the responses to angiotensin II between cardiac myocytes and nonmyocytes. Methods: Primary cultures of neonatal rat cardiac myocytes and nonmyocytes were prepared. [Ca2+](i) was measured with indo-1. Cellular growth was assayed by [H-3]thymidine uptake, RNA content, [H-3]phenylalanine incorporation and protein content. Induction of immediate-early gene was examined by Northern blot analysis. Results: In myocytes, angiotensin II decreased [Ca2+](i) transients, induced c-fos mRNA, and accelerated hypertrophy. These effects were completely suppressed by AT(1) receptor blockade or protein kinase C inhibition. After chelation of extracellular Ca2+, angiotensin II caused no change in [Ca2+](i) or no induction of c-fos in myocytes. Phorbol 12-myristate 13-acetate also decreased [Ca2+](i) transients, caused c-fos induction, and provoked hypertrophy in myocytes. In nonmyocytes, angiotensin II increased [Ca2+](i) transiently, induced c-fos mRNA and hypertrophy. These effects of angiotensin II were not fully abolished by protein kinase C inhibition. Extracellular Ca2+ chelation did not completely inhibit the effects of angiotensin II on [Ca2+](i) or c-fos induction 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 cellular hypertrophy and immediate-early genes through the activation of protein 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 mediated by a transient increase in [Ca2+](i) which acts synergistically with protein kinase C activation.