Nifedipine inhibits angiotensin II-induced cardiac fibrosis via downregulating Nox4-derived ROS generation and suppressing ERK1/2, JNK signaling pathways.

Nifedipine, a classic L-type dihydropyridine calcium channel blocker (CCB), has been reported to possess multiple cardioprotective properties. However, little is known about the effects of nifedipine on cardiac fibrosis induced by angiotensinII (AngII) and the detailed molecular mechanisms. In this study, we found that nifedipine attenuated AngII-induced cardiac fibrosis in vitro via inhibiting the proliferation, differentiation of cardiac fibroblasts and antagonizing the upregulation of extracellular matrix (ECM) protein fibronectin (FN) and the pro-fibrotic cytokine connective tissue growth factor (CTGF). Furthermore, nifedipine suppressed the upregulation of NAD(P)H oxidase 4 (Nox4) and the production of reactive oxygen species (ROS) induced by AngII. In addition, it markedly inhibited the phosphorylation of extracellular signal-regulate kinases 1/2 (ERK1/2) and c-Jun NH(2)-terminal kinase (JNK) stimulated by AngII. However, nifedipine exhibited no effect on the variation of intracellular Ca2+ concentration ([Ca2+]i). These results suggested that (1) nifedipine inhibited cardiac fibrosis induced by AngII; (2) the anti-fibrotic effects of nifedipine may be mediated by interfering with the production of ROS and the activation of ERK1/2 and JNK signaling pathways; (3) the classic calcium channel blocking action of nifedipine may not be involved in the anti-fibrotic activities.