Phospholipase C/protein kinase C pathway mediates angiotensin II-dependent apoptosis in neonatal rat cardiac fibroblasts expressing AT1 receptor

Cardiac fibroblasts are the major non-myocyte cell constituent in the myocardium, and they are involved in heart remodeling. Angiotensin II type I receptor (AT(1)R), and changes in its expression have been reported in cardiac fibroblasts after myocardial infarction. However, the AT(1)R-dependent signaling pathways involved in cardiac fibroblast death remain unknown. Using adenovirus, we ectopically expressed AT(1)R in cultured neonatal rat cardiac fibroblasts and investigated the role of the phospholipase (PLC)/protein kinase C (PKC) pathway on Ang II-dependent death. Ang II induced cardiac fibroblast death characterized by an early loss of mitochondrial membrane potnetial, increased Bax/Bc1-2 ratio, caspase-3 activation, and DNA fragmentation. All these effects were prevented by the AT(1)R antagonist losartan, PLC inhibitor U73122, and PKC inhibitor G06976. We conclude that Ang II stimulates the intrinsic apoptotic pathway in cultured cardiac fibroblasts by the AT(1)R/PLC/PKC signaling pathway.