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 hypertrophy. The aim of the present study was to test whether calcineurin is involved in the signal transduction of angiotensin II (Angll)-induced cardiac myocyte hypertrophy and fibroblast hyperplasia. Firstly, we observed that calcineurin activity was significantly increased in Angll-stimulated cardiac myocytes as well as fibroblasts, but was markedly inhibited by Losartan (50μmol/l), H7 (50μmol/l), and Fura-2/AM (5μmol/l). It is indicated that Angll-induced activation of calcineurin is through an ATI receptor, may be dependent on the sustained increases of [Ca2+]i, and be regulated by protein kinase C. In a second experiment, we found that cyclosporin (0.1–10 μmol/l), a specific inhibitor of calcineurin, decreased the protein synthesis rate in Angll-stimulated cardiomyocytes and the DNA synthesis rate in Angll-treated fibroblasts in a dosedependent manner. In the latter experiment, calcineurin inhibition reduced the mRNA level of the atrial natriuretic factor gene. These results indicate that calcineurin is involved in the signal transduction of Angll-induced cardiomyocyte hypertrophy and fibroblast hyperplasia.