The protooncogene c-myc is involved in the regulation of cell growth. Although increased c-Myc expression is found in hypertrophied hearts, the role of c-Myc in the development of cardiac hypertrophy (CH) has never been determined. The aim of this study was to test the effect of heart-specific inhibition of c-Myc expression on the development of coldinduced cardiac hypertrophy (CICH). We hypothesized that heart-specific inhibition of c-Myc expression attenuates CICH. We constructed c-Myc antisense (c-MycAS) plasmid and green fluorescent protein (GFP) plasmid driven by a heartspecific promoter, a-myosin heavy chain (MHC). The cell culture study indicated that c-MycAS can effectively inhibit c-Myc expression and that GFP can express in the rat heart cells. Four groups of rats were used to test the effect of in vivo inhibition of cardiac c-Myc expression on the development of CICH. Three groups received an intravenous injection of c-MycAS, GFP and buffer, respectively, at the beginning of exposure to moderate cold (6.71C), while the last group received buffer and was kept at room temperature (251C) to serve as a control. Blood pressure (BP) of the cold-exposed groups receiving buffer or GFP increased significantly, whereas BP of the c-MycAS group did not increase until 28 days after exposure to cold. Thus, c-MycAS delayed and attenuated cold-induced hypertension (CIH). The antihypertensive effect of c-MycAS was probably due to the decreased cardiac output. Magnetic resonance imaging (MRI) showed that the in vivo left ventricle wall thickness of cold-exposed rats was decreased significantly by c-MycAS. Consistently, the cold-induced increase in heart weight was attenuated by inhibition of cardiac c-Myc expression. The heart specificity of a-MHC promoter was confirmed by the selective inhibition of c-Myc expression in the heart and by the selective expression of both GFP mRNA and GFP protein in the heart. Heartspecific inhibition of c-Myc expression attenuated the development of CICH. The increased c-Myc expression may play a critical role in the pathogenesis of CICH. Thus, heart-specific inhibition of c-Myc expression may be a new and effective approach for the control of CH.

Background: Our recent study showed that inhibition of MR prevented progression of cold‐induced hypertension (CIH) and attenuated renal damage. The aim of this study was to investigate the role of MR in the onset and development of CIH. Methods and results: Recombinant adeno‐associated virus (AAV) carrying a short hairpin small interference RNA for MR (AAV.MR‐shRNA) or a scrambled sequence (AAV.control‐shRNA) was constructed. Six groups of mice were used (6 mice/group). Three groups were exposed to moderate cold (6.7°C) while the remaining three groups were kept at room temperature (RT, warm) as controls. In each temperature condition, 3 groups received IV injection of AAV.MR‐shRNA (0.35×1011 particles/mouse, 0.5 ml), AAV.Control‐shRNA (0.35×1011 particles/mouse, 0.5 ml), or virus‐free PBS (0.5 ml), respectively, prior exposure to cold. Blood pressure (BP) of the mice treated with AAV.control‐shRNA or PBS increased significantly within 4 days of exposure to cold whereas BP of the cold‐exposed AAV.MR‐shRNA‐treated mice did not increase and remained at the level of the control group maintained at RT. Thus, AAV delivery of MR‐shRNA prevented the development of CIH. AAV.MR‐shRNA significantly attenuated cardiac and renal hypertrophy. MR was effectively silenced as evidenced by a significant decrease in MR protein expression in the heart and kidneys of cold‐exposed AAV.MR‐shRNA‐treated mice. The inhibition of MR also resulted in significant decreases in endothelin‐1 (ET‐1) production, g91phox expression and O2− production in the heart and kidneys in cold‐exposed mice. Conclusion: MR plays an important role in the initiation and development of CIH. The role of MR in CIH may be mediated by ET‐1 and NADPH oxidase.