Abstract 721: Proto-Oncogene c-myc, a Novel Therapeutic Target for Cardiac Hypertrophy
Background: 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 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 cold-induced cardiac hypertrophy (CICH), a natural form of cardiac hypertrophy. We hypothesized that heart-specific inhibition of c-Myc expression attenuates CICH.
Methods and Results: We constructed c-Myc antisense (c-MycAS) plasmid and GFP plasmid driven by a heart-specific promoter, α-MHC. The cell culture study indicated that c-MycAS can selectively inhibit c-Myc expression and that GFP can selectively 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, before exposure to cold (44°F), while the last group received buffer and was kept at room temperature (RT) 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 driven by a heart-specific promoter 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 was decreased by c-MycAS at day 18 when cardiac c-Myc expression was inhibited by c-MycAS. Consistently, the cold-induced increase in heart weight was decreased by c-MycAS at day 18. The heart specificity of α-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.
Conclusion: Heart-specific inhibition of c-Myc expression attenuated the development of CIH and CICH. The increased c-Myc expression plays a key role in the pathogenesis of CICH. Thus, heart-specific inhibition of c-Myc expression may provide a new and effective approach for the control of cardiac hypertrophy.