Role of Activating Transcription Factor 3 in the Protective Effect of Resveratrol in Cardiomyocytes

Adriamycin, one of the original anthracyclines, remains among the most effective anticancer drugs ever developed. Clinical use of adriamycin is, however, greatly limited by its serious adverse cardiac effects that may ultimately lead to cardiomyopathy and heart failure. Therefore, it is important to develop agents that inhibit cardiotoxicity induced by adriamycin and, as a result, benefit cardiac dysfunction. Activating transcription factor (ATF)-3, a member of the ATF/cyclic adenosine monophosphate (cAMP)-responsive element binding protein (ATF/CREB) family of transcription factors, is induced by a wide range of stress stimuli. ATF-3 may function as a cytoprotective transcription factor in adriamycin-treated cardiac myocytes. Resveratrol is a major component of the polyphenols from grapes and red wine. We have demonstrated that resveratrol inhibits angiotensin II-induced cardiomyocyte hypertrophy and cyclic strain-induced endothelin-1 expression in vascular endothelial cells. Resveratrol has been found to be effective in protecting against pathological states characterized by an increase in basal rate of reactive oxygen species (ROS) production in hearts, but the mechanism by which it exerts the cardioprotective effect is not well established. In addition, it has been reported that resveratrol induces the expression of ATF-3 in HCT-116 human colorectal cancer cells. However, the role of ATF-3 in resveratrol’s effect still remains unclear. In this project, the applicant intends to investigate the influence of resveratrol on adriamycin-induced aoptosis in rat cardiomyocytes. The applicant will examine the effect of resveratrol on adriamycin-induced cardiomyocyte apoptosis and explore its molecular mechanism in culture system; and observe effects of resveratrol on adriamycin-induced cardiotoxicity, and investigate the role of ATF-3 in resveratrol’s inhibitory effect on adriamycin-induced cardiomyocyte apoptosis and explore its molecular mechanism in culture system.