Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice
Inhibition of ischemic cardiomyocyte apoptosis through targeted ablation of Bnip3 restrains postinfarction remodeling in mice
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DOI：
10.1172/jci32490
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发表时间：
2007-10-01
影响因子：
15.9
通讯作者：
Dorn, Gerald W., II
中科院分区：
文献类型：
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作者：
Diwan, Abhinav;Krenz, Maike;Dorn, Gerald W., II
心肌梗死后，非缺血性心肌细胞死亡导致梗死范围扩大、心肌丧失和心室功能障碍。在这里，我们证明了一个特定的促凋亡基因，Bnip 3，最大限度地减少心室重塑小鼠，尽管没有影响早期或晚期梗死面积。我们评估了切除Bnip 3对小鼠手术缺血/再灌注（IR）损伤后心肌细胞死亡、梗死面积和心室重塑的影响。在IR之后，在Bnip 3（-/-）和WT小鼠之间没有观察到显著差异。然而，在IR后2天，Bnip 3（-/-）梗死周围和远端心肌的细胞凋亡减少，并且在IR后3周，Bnip 3（-/-）小鼠表现出保留的LV收缩性能，减少的LV扩张和减少的心室球形化。这些结果表明通过抑制细胞凋亡来挽救心肌。在非应激小鼠中，Bnip 3的强制心脏表达增加了心肌细胞凋亡，导致进行性LV扩张和收缩功能下降。冠状动脉结扎前条件性Bnip 3过表达增加了细胞凋亡和梗死面积。这些研究确定心肌Bnip 3作为梗死心脏心室重构的主要决定因素的缺血后细胞凋亡，表明Bnip 3可能是一个有吸引力的治疗靶点。
Following myocardial infarction, nonischemic myocyte death results in infarct expansion, myocardial loss, and ventricular dysfunction. Here, we demonstrate that a specific proapoptotic gene, Bnip3, minimizes ventricular remodeling in the mouse, despite having no effect on early or late infarct size. We evaluated the effects of ablating Bnip3 on cardiomyocyte death, infarct size, and ventricular remodeling after surgical ischemia/reperfusion (IR) injury in mice. Immediately following IR, no significant differences were observed between Bnip3(-/-) and WT mice. However, at 2 days after IR, apoptosis was diminished in Bnip3(-/-) periinfarct and remote myocardium, and at 3 weeks after IR, Bnip3(-/-) mice exhibited preserved LV systolic performance, diminished LV dilation, and decreased ventricular sphericalization. These results suggest myocardial salvage by inhibition of apoptosis. Forced cardiac expression of Bnip3 increased cardiomyocyte apoptosis in unstressed mice, causing progressive LV dilation and diminished systolic function. Conditional Bnip3 overexpression prior to coronary ligation increased apoptosis and infarct size. These studies identify postischemic apoptosis by myocardial Bnip3 as a major determinant of ventricular remodeling in the infarcted heart, suggesting that Bnip3 may be an attractive therapeutic target.