Inhibition of ischemia induced-apoptosis in cardiac myocytes by ATF3 and its implication in gene therapy

点击翻译按钮获取中文摘要

ATF3 (activating transcription factor 3) is a member of the ATF/CREB family, which binds to CRE and AP-1 consensus sequences. We have recently reported that ATF3 inhibits apoptosis of cultured neonatal rat cardiac myocytes induced by DOX. ATF3 was immediately induced at transcriptional and translational level by stimulation of DOX, peaking at 1 hour and at 3 hours respectively. To extend our understanding of the physiological functions of ATF3 in the DOX-induced apoptosis, we produced the adenovirus vector containing coding sequences of ATF3 (AdATF3) and directed overexpression of ATF3 in cardiac myocytes. The inhibition of DOX-induced apoptosis by AdATF3 was shown by flow cytometry, cefi viabih'ty assay and TUNEL staining analyzes. We further demonstrated that ATF3 formed heterodimer with c-Jun both in the cells with or without DOX treatment, suggesting that inappropriate formation of hetero- and homodimer of ATF3 may result in the inhibition of apoptosis in cardiac myocytes with AdATF3.We further investigated AdATF3 can inhibit apoptosis induced by ischemia in cardiac myocytes. AdATF3 inhibited apoptosis induced by hypoxic stimulation in vitro. We also showed that AdATF3 inhibited apoptosis induced by ischemia-reperfusion.In conclusion, these results indicate that overexpression of ATF3 inhibits apoptosis in cardiac myocytes, and suggest a cardio protective role of ATF3. Our data may open a new avenue for gene therapy against myocardial damage by a variety of cardiovascular diseases.