Heart Failure: From Protein to Phenotype

Background: Heart failure is a leading cause of death in industrialized nations especially in the aging populations. Novel approaches to treat the heart after acute injury and to improve cardiac hypertrophic remodeling and heart failure processes remain unsatisfactory. Activating transcription factor 3 (ATF3) is a member of the ATF/cAMPresponse elementbinding protein family of transcriptional factors. It can be induced by stress condition in a variety of tissues, including cardiac hypertrophy. However, the role of ATF3 or miRsregulated ATF3 as therapeutic approaches for cardiac hypertrophic remodeling and heart failure is still unclear. Methods and Results: Our recent study revealed that ATF3 can protect against pressure overload-induced heart failure. We demonstrated that ATF3 KO mice has rapid progression to cardiac dilation without proper hypertrophic remodeling after trans-aortic banding (TAB), we then infused tert-butylhydroquinone, a selective ATF3 inducer, which inhibited TAB induced cardiac dilatation and increased left ventricular contractility thus rescue heart failure. We used IPA database analysis to identify the miRsregulated ATF3 as therapeutic approaches for cardiac hypertrophic remodeling. One specific miRNA, miR-494, initially found in human retinoblastoma tissue, was identified and confirmed to have direct interaction with ATF3 in our H9C2 cells. We then generated miR-494 transgenic mice and demonstrated that miR-494 can be specifically expressed in the heart tissue in our miR-494 transgenic mice. We found that ATF3 expression were markedly decrease in miR-494 transgenic mice receiving TAB treatment as compared to wild type (WT) mice, at 8 weeks and 12 weeks periods after TAB treatment. In addition, echocardiography data showed impaired LV contractility with worsen left ventricular chamber dilatation and wall thinning in miR-494 transgenic mice as compared to WT TAB mice, 12 weeks after TAB treatment. Cardiac hypertrophic markers, including atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and b-MHC, were decreased in miR-494 transgenic mice 8 week after TAB, but not in the WT mice. In addition, down regulation of SIRT1 was observed in miR-494 mice after 8 week, post TAB treatment compared to WT. Conclusions: These results suggest that miR-494 repressed ATF3 expression in cardiac hypertrophic remodeling via suppressing beneficial hypertrophic markers in vivo. Therefore, suppression of this specific miR-494-ATF3 signaling pathway thus to activate ATF3 expression may ameliorate heart failure in cardiac hypertrophic remodeling and can be a potential therapeutic target.