Angiotensin II signalling and calcineurin in cardiac fibroblasts: differential effects of calcineurin inhibitors FK506 and cyclosporine A

摘要

Introduction: Cardiac remodelling is controlled by complex systems, including activation of the renin-angiotensin system (RAS) and signalling through MAP kinases and Ca2+-activated calcineurin. Whether Ang II, which increases [Ca2+]i and stimulates MAP kinases, mediates myocardial effects through calcineurin-dependent pathways remain unclear. We investigated effects of two calcineurin inhibitors, cyclosporine A (CsA) and tacrolimus (FK506) (10-10-10-6 mol/L, 20 mins) on activation of MAP kinases and on growth, pro-fibrotic and pro-inflammatory responses in Ang II-stimulated rat cardiac fibroblasts. Methods and Results: Ang II increased phosphorylation of ERK1/2 and p38MAPK (1.5-1.8-fold, p Conclusions: Our findings identify an important role for calcineurin in MAP kinase/growth/pro-fibrotic/pro-inflammatory signalling by Ang II in cardiac fibroblasts. Although both FK506 and CsA inhibit calcineurin, they exert differential effects on molecular and cellular responses. Such differences may contribute to variable clinical responses of these agents.