Cardiovascular Research Advance Access [Accepted Manuscript] published online on July 2, 2008
Cardiovascular Research, doi:10.1093/cvr/cvn183
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Cardiomyocyte proliferation and protection against post-myocardial infarction heart failure by cyclin D1 and Skp2 ubiquitin ligase
1 Department of Biochemical Genetics, Medical Research Institute and Laboratory for Gene Structure and Regulation, School of Biomedical Science, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8510, Japan
2 Biomedical Research Laboratories, Asubio Pharma Co., Ltd., 1-1-1, Wakayamadai, Shimamoto-cho, Mishima-gun, Osaka, 618-8503, Japan
3 Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
4 Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan
Correspondence should be addressed to M. T-A. (mtam.bgen{at}mri.tmd.ac.jp) or S.K. (kita.bgen{at}mri.tmd.ac.jp), Tel: +81-3-5803-5823; Fax +81-3-5803-0248.
Aims: Cyclins and other cell cycle regulators have been used in several studies to regenerate cardiomyocytes in ischemic heart failure. However proliferation of cardiomyocytes induced by nuclear-targeted cyclin D1 (D1NLS), stops after 1 or 2 rounds of cell cycles due in part to accumulation of p27Kip1, an inhibitor of cyclin- dependent kinase (CDK). Thus, expression of S-phase kinase-associated protein 2 (Skp2), a negative regulator of p27Kip1, significantly enhances the effect of D1NLS and CDK4 on cardiomyocyte proliferation in vitro. Here, we examined whether Skp2 can also improve cardiomyocyte regeneration and post-ischemic cardiac performance in vivo.
Methods and Results: Wistar rats underwent ischemia/reperfusion injury by ligation of the coronary artery followed by injection of adenovirus vectors for D1NLS and CDK4 with or without Skp2. Enhanced proliferation of cardiomyocytes in the presence of Skp2 was demonstrated by increased expression of Ki67, a marker of proliferating cells (1.95% vs 4.00%), and mitotic phosphorylated histone H3 (0.24% vs 0.58%). Compared to rats that received only D1NLS and CDK4, expression of Skp2 improved left ventricular function as measured by the maximum and minimum rates of change in left ventricular pressure, the left ventricle end-diastolic pressure, left ventricle end-diastolic volume index, and the lung/body weight ratio.
Conclusions: Expression of Skp2 enhanced the effect of D1NLS and CDK4 on the proliferation of cardiomyocytes and further contributed to improved post-ischemic cardiac function. Skp2 might be a versatile tool to improve the effect of cyclins on post-ischemic regeneration of cardiomyocytes in vivo.
KEYWORDS cardiac regeneration; cell cycle; mitotic proliferation; cyclin D1; Skp2
Time for primary review: 30
* These authors contributed equally to this work.
Abbreviations: CDK, cyclin dependent kinase: NLS, nuclear localization signal: H3P, phosphorylated histone H3: MI, myocardial infarction; FS, fractional shortening
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Cardiovasc Res 2008 80: 161-162.
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