Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy

M. Bello Roufai, H. Li, Zhongjie Sun

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1406-1416
Number of pages11
JournalGene Therapy
Volume14
Issue number19
DOIs
StatePublished - Oct 1 2007

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Cardiomegaly
Green Fluorescent Proteins
Buffers
Myosin Heavy Chains
Plasmids
Blood Pressure
Intravenous Injections
Cardiac Output
Antihypertensive Agents
Heart Ventricles
Cell Culture Techniques
Magnetic Resonance Imaging
Hypertension
Weights and Measures
Messenger RNA
Temperature

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Heart-specific inhibition of protooncogene c-myc attenuates cold-induced cardiac hypertrophy. / Bello Roufai, M.; Li, H.; Sun, Zhongjie.

In: Gene Therapy, Vol. 14, No. 19, 01.10.2007, p. 1406-1416.

Research output: Contribution to journalArticle

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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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