Endothelin-1 Stimulates Cardiac Fibroblast Proliferation Through Activation of Protein Kinase C,

L. Piacentini, M. Gray, N. Y. Honbo, J. Chentoufi, M. Bergman and J. S. Karliner. Endothelin-1 Stimulates Cardiac Fibroblast Proliferation Through Activation of Protein Kinase C. Journal of Molecular and Cellular Cardiology (2000) 32, 565–576. After myocardial ischemia, circulating levels of the mitogen endothelin-1 (ET-1) increase. The effects of ET-1 on cardiac fibroblasts are poorly characterized. Therefore we examined the influence of ET-1 on cardiac fibroblast proliferation with a view to elucidating the signal transduction mechanisms underlying this effect. ET-1 (10 n ) stimulated [3H]thymidine incorporation and cell proliferation in cultured neonatal rat cardiac fibroblasts, consistent with its activity as a mitogen. We examined the role of protein kinase C (PKC) on this function. Inhibition of PKC activation with either chelerythrine (1 μ m) or staurosporine (1 n ) attenuated ET-1-induced increases in DNA synthesis and cell number. Downregulation of PKC by chronic pretreatment with 10 n phorbol 12-myristate 13-acetate (PMA) also prevented ET-1-induced mitogenesis. In contrast to previous reports that cardiac fibroblast proliferation stimulated by angiotensin II acts independently of PKC, the ET-1 mediated mitogenic effect requires activation of PKC in these cells. Findings in adult rat cardiac fibroblasts were identical. In addition, we noted that concurrent treatment with the pro-inflammatory cytokine interleukin 1 β which, like ET-1, is released after myocardial ischemia, attenuated the ET-1-induced increases in DNA synthesis and cell number. This effect was not mediated through a nitric oxide synthase pathway.