Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice
Histone deacetylase inhibition reduces myocardial ischemia-reperfusion injury in mice
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DOI：
10.1096/fj.08-108548
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发表时间：
2008-10-01
期刊：
影响因子：
4.8
通讯作者：
Gruber, Peter J.
中科院分区：
文献类型：
--
作者：
Granger, Anne;Abdullah, Ibrahim;Gruber, Peter J.
限制梗死范围是急性冠脉综合征治疗的主要目标，研究的重点是实现梗死相关血管的快速通畅。然而，对缺血期间表观遗传修饰的新理解表明，还没有广泛探索的其他靶向治疗方法。在此，我们发现在体外和体内，缺血通过组蛋白H3/4的脱乙酰基来诱导组蛋白脱乙酰酶(HDAC)的活性。我们利用标准的小鼠缺血-再灌注模型显示，即使在缺血损伤后1小时给药，化学HDAC抑制剂也能显著减少梗塞面积。我们证明，在体内和体外，HDAC抑制剂可以阻止缺血诱导的基因程序的激活，包括缺氧诱导因子-LOT、细胞死亡和血管通透性，从而为解释减少血管泄漏和心肌损伤提供了潜在的机制。在体外，siRNA敲除实验表明HDAC4是缺血心肌细胞中这种作用的介体。这些结果表明，HDAC抑制剂改变了心脏对缺血损伤的反应，并缩小了梗死面积，为急性冠状动脉综合征提供了新的治疗方法。
Limitation of infarct size is a major goal of therapy for acute coronary syndromes, and research has focused on achieving rapid patency of infarct-related vessels. However, new understandings of epigenetic modifications during ischemia suggest additional targeted approaches that have not been extensively explored. Here, we show that ischemia induces histone deacetylase (HDAC) activity in the heart with deacetyladon of histones H3/4 in vitro and in vivo. We show, utilizing a standard murine model of ischemia-reperfusion, that chemical HDAC inhibitors significantly reduce infarct area, even when delivered 1 h after the ischemic insult. We demonstrate that HDAC inhibitors prevent ischemia-induced activation of gene programs that include hypoxia inducible factor-lot, cell death, and vascular permeability in vivo and in vitro, thus providing potential mechanisms to explain reduced vascular leak and myocardial injury. In vitro, siRNA knockdown experiments implicate HDAC4 as a mediator of the effects in ischemic cardiac myocytes. These results demonstrate that HDAC inhibitors alter the response to ischemic injury in the heart and reduce infarct size, suggesting novel therapeutic approaches for acute coronary syndromes.