Abstract
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 cold-induced 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 heart-specific promoter, α-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 (6.7°C), while the last group received buffer and was kept at room temperature (25°C) 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 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. Heart-specific 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.
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Accession codes
Abbreviations
- MHC:
-
myosin heavy chain
- SNS:
-
sympathetic nervous system
- RAS:
-
rennin-angiotensin system
- ANF:
-
atria natriuretic factor
- OCT:
-
compound, optimal cutting temperature compound
- NBF:
-
neutral-buffered formalin
- ECG:
-
electrocardiogram.
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Acknowledgements
This work was supported by NIH R01 077490 (NHLBI). We thank Drs Jeffrey Robbins and Jim Gulick (University of Cincinnati, Cincinnati, USA) for providing us with α-MHC promoter.
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Bello Roufai, M., Li, H. & Sun, Z. Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy. Gene Ther 14, 1406–1416 (2007). https://doi.org/10.1038/sj.gt.3302995
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DOI: https://doi.org/10.1038/sj.gt.3302995
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