Requirement for protein kinase C in reactive oxygen species-induced apoptosis of vascular smooth muscle cells

Article

关键词: HYDROGEN-PEROXIDE;    DEATH;    ACTIVATION;    EXPRESSION;    ISOZYME;    BCL-2;    SUPPRESSION;    MODULATION;    ISOFORMS;   

DOI  :  10.1161/01.CIR.100.9.967

来源: SCIE

【 摘 要 】

Background-Vascular smooth muscle cell (VSMC) apoptosis is a component of a variety of cardiovascular diseases and may be related to reactive oxygen species (ROS). This study was designed to deter mine the role of protein kinase C (PKC) in ROS-induced VSMC apoptosis, Methods and Results-Rat aortic VSMCs were exposed to H2O2, and the nature of cell death was characterized in the absence or presence of different PKC inhibitors. The results demonstrate that exposure of VSMCs to H2O2, led to a dose-dependent (25 to 100 mu mol/L) and time-dependent (peal, at 2 minutes) activation of PKC. Among the PKC isoforms alpha, beta, delta, epsilon, and zeta, only PKC-alpha and PKC-epsilon were found to change their intracellular distribution on H2O2 treatment. Apoptosis was the predominant form of cell death when PKC had been activated by H2O2 alone or by H2O2 in the presence of 50 nmol/L phorbol 12-myristate 13-acetate. In contrast, necrosis became the predominant form of cell death when PKC had been downregulated by prolonged exposure to 200 nmol/L phorbol 12,13-dibutyrate or inhibited by 50 nmol/L staurosporine, 100 nmol/L calphostin C, or 30 mu mol/L H-7, In addition, caspase-3 was activated in H2O2-induced VSMC apoptosis but not when PKC was downregulated or inhibited, Inhibition of caspase-3 by 50 mu mol/L Ac-DEVD-CHO could significantly attenuate H2O2-induced apoptosis and was not associated with the induction of necrosis. Conclusions-We conclude that in VSMCs, PKC converts the ROS-induced signals from necrotic cell death to the activation of an apoptotic cell death program. These data imply a novel and important role of PKC for the pathogenesis of such vascular diseases as atherosclerosis, restenosis, and hypertension.

【 授权许可】

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