Proapoptotic effects of ANG II in human coronary artery endothelial cells:role of AT(1) receptor and PKC activation

Anoxia-reoxygenation, tumor necrosis factor-alpha (TNF-alpha), and angioten sin II (ANG II) have been shown to induce apoptosis in myocytes. However, t he role of these mediators in causing apoptosis of human coronary artery en dothelial cells (HCAEC) is not known. This study was designed to examine th e interaction of these mediators in induction of apoptosis in HCAEC. Cultur ed HCAEC were exposed to anoxia-reoxygenation, TNF-alpha, and ANG II. TNF-a enhanced apoptosis of HCAEC (determined by DNA nick-end labeling in situ a nd DNA laddering) caused by anoxia-reoxygenation. ANG II increased apoptosi s beyond that caused by anoxia-reoxygenation and TNF-alpha. Apoptosis cause d by ANG II was reduced by losartan, a specific ANG II type 1 receptor (AT( 1)R) blocker, whereas PD-123,177, a specific ANG II type 2 receptor blocker , under identical conditions had minimal effect. The proapoptotic effects o f ANG II were associated with the activation of protein kinase C (PKC). The importance of PKC activation as a signal transduction mechanism became evi dent in experiments wherein treatment of HCAEC with a specific inhibitor of PKC activation decreased ANG II-mediated apoptosis. Thus AT(1)R activation appears to be responsible for apoptosis caused by ANG II in HCAEC, and AT( 1)R activation-mediated apoptosis involves activation of PKC.