Involvement of calcineurin in angiotensin II-induced cardiomyocyte hypertrophy and cardiac fibroblast hyperplasia of rats

A rapidly emerging body of literature implicates a pivotal role for the Ca2 +-calmodulin-dependent phosphatase, calcineurin, as a cellular target for a variety of Ca2+-dependent signaling pathways culminating in cardiac hypert rophy. The aim of the present study was to test whether calcineurin is invo lved in the signal transduction of angiotensin II (AngII)-induced cardiac m yocyte hypertrophy and fibroblast hyperplasia. Firstly, we observed that ca lcineurin activity was significantly increased in AngII-stimulated cardiac myocytes as well as fibroblasts, but was markedly inhibited by Losartan (50 mu mol/l), H-7 (50 mu mol/l), and Fura-2/AM (5 mu mol/l). It is indicated that AngII-induced activation of calcineurin is through an AT1 receptor, ma y be dependent on the sustained increases of [Ca2+](i), and be regulated by protein kinase C. In a second experiment, we found that cyclosporin (0.1-1 0 mu mol/l), a specific inhibitor of calcineurin, decreased the protein syn thesis rate in AngII-stimulated cardiomyocytes acid the DNA synthesis rate in AngII-treated fibroblasts in a dose-dependent manner. In the latter expe riment, calcineurin inhibition reduced the mRNA level of the atrial natriur etic factor gene. These results indicate that calcineurin is involved in th e signal transduction of AngII-induced cardiomyocyte hypertrophy and fibrob last hyperplasia.