Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats
Regional expression of the hypoxia-inducible factor (HIF) system and association with cardiomyocyte cell cycle re-entry after myocardial infarction in rats
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DOI：
10.1007/s00380-007-1029-2
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发表时间：
2008-05-01
影响因子：
1.5
通讯作者：
Ma, Da-Lie
中科院分区：
文献类型：
--
作者：
Bai, Chen-Guang;Liu, Xiao-Hong;Ma, Da-Lie
缺氧诱导因子(HIF)-1 α和-2 α对心肌有不同的作用，但对心肌细胞的直接作用的重要性尚不清楚。为了明确心肌梗死（MI）后心肌细胞周期变化与心肌细胞区域积累的关系，我们采用冠状动脉闭塞法建立了大鼠心肌梗死模型。为了进一步证明HIF与细胞周期调节之间的因果关系，我们用携带HIF-1 α和HIF-2 α的腺病毒载体转染培养的心肌细胞。心肌梗死后2周，梗死左心室和非梗死左心室HIF-1 α和HIF-2 α mRNA均中度升高；在室间隔和右心室区域也检测到HIF-2 α扩增。与mRNA水平的变化相一致，HIF-1 α和HIF-2 α的免疫组化信号具有不同的区域分布特征。在梗死组织邻近心肌中，HIF-1 α和HIF-2 α与Ki-67标记指数呈显著相关（P < 0.001）。免疫组化双染色显示HIF阳性心肌细胞进行了DNA合成。HIF-1 α或-2 α处理的心肌细胞在体外有效表达Ki-67、磷酸组蛋白H3和溴脱氧尿苷。综上所述，HIF-1 α和HIF-2 α在缺血性心脏病大鼠模型中具有明显的空间表达模式。这两种HIF亚基可能是心肌细胞重新进入细胞周期和启动DNA合成的有效刺激。
Hypoxia-inducible factor (HIF)-1 alpha and-2 alpha have diverse actions on the myocardium, but the importance of direct effects on cardiac myocytes is unclear. To define their regional accumulation and association with cardiomyocyte cell cycle change after myocardial infarction (MI), a rat MI model was established by occluding the coronary arteries. To further prove a causative relationship between HIF and cell cycle regulation, cultured cardiomyocytes were transfected with adenoviral vectors carrying HIF-1 alpha and HIF-2 alpha. Two weeks after MI, both HIF-1 alpha and HIF-2 alpha mRNA were moderately increased in the infarcted left ventricle and noninfarcted left ventricle; HIF-2 alpha amplification was also detected in areas of the interventricular septum and the right ventricle. In concordance with the changes in mRNA levels, immunohistochemistry signals of HIF-1 alpha and HIF-2 alpha were characterized by different regional distributions. In the myocardium adjacent to the infarcted tissue, a significant correlation between HIF-1 alpha or HIF-2 alpha and Ki-67 labeling index was observed (P < 0.001). Immunohistochemical double staining showed that HIF positive cardiomyocytes underwent DNA synthesis. Cardiomyocytes treated with HIF-1 alpha or -2 alpha expressed Ki-67, phosphohistone H3, and bromodeoxyuridine effectively in vitro. In conclusion, HIF-1 alpha and HIF-2 alpha had a distinct spatial expression pattern in a rat model of ischemic heart disease. Both HIF subunits might be potent stimuli for cardiomyocytes to re-enter the cell cycle and initiate DNA synthesis.