Cardiomyocyte proliferation and protection against post-myocardial infarction heart failure by cyclin D1 and Skp2 ubiquitin ligase
Cardiomyocyte proliferation and protection against post-myocardial infarction heart failure by cyclin D1 and Skp2 ubiquitin ligase
复制标题
DOI：
10.1093/cvr/cvn183
复制
发表时间：
2008-11-01
影响因子：
10.8
通讯作者：
Kitajima, Shigetaka
中科院分区：
文献类型：
--
作者：
Tamamori-Adachi, Mimi;Takagi, Hiromitsu;Kitajima, Shigetaka
细胞周期蛋白和其他细胞周期调节剂已被用于几项研究，以再生缺血性心力衰竭的心肌细胞。然而，由核靶向细胞周期蛋白D1（D1 NLS）诱导的心肌细胞增殖在一个或两个细胞周期后停止，部分原因是细胞周期蛋白依赖性激酶（CDK）抑制剂p27 Kip 1的积累。因此，S期激酶相关蛋白2（Skp 2）的表达，p27 Kip 1的负调节，显着增强D1 NLS和CDK 4对心肌细胞增殖的影响在体外。在这里，我们研究是否Skp 2也可以提高心肌细胞再生和缺血后的心脏性能在vivo.Methods和结果Wistar大鼠缺血/再灌注损伤结扎冠状动脉，然后注射腺病毒载体D1 NLS和CDK 4或没有Skp 2。在Skp 2存在下，心肌细胞的增殖增强通过增殖细胞的标志物Ki 67（1.95%对4.00%）和有丝分裂磷酸化组蛋白H3（0.24%对0.58%）的表达增加来证明。与仅接受D1 NLS和CDK 4的大鼠相比，Skp 2的表达改善了左心室功能，如通过左心室压力、左心室舒张末期压力、左心室舒张末期容积指数和肺/结论Skp 2的表达增强了D1 NLS和CDK 4对心肌细胞增殖的影响，并进一步促进了心肌细胞的增殖。改善缺血后心脏功能。Skp 2可能是一个通用的工具，以提高细胞周期蛋白对心肌细胞缺血后再生的影响在体内。
Aims Cyclins and other cell-cycle regulators have been used in several studies to regenerate cardiomyocytes in ischaemic heart failure. However, proliferation of cardiomyocytes induced by nuclear-targeted cyclin D1 (D1NLS) stops after one or two 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-ischaemic cardiac performance in vivo.Methods and results Wistar rats underwent ischaemia/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 with 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.Conclusion Expression of Skp2 enhanced the effect of D1NLS and CDK4 on the proliferation of cardiomyocytes and further contributed to improved post-ischaemic cardiac function. Skp2 might be a versatile tool to improve the effect of cyclins on post-ischaemic regeneration of cardiomyocytes in vivo.