Suppression of Excessive Histone Deacetylases Activity in Diabetic Hearts Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondria Apoptosis Pathway.
Suppression of Excessive Histone Deacetylases Activity in Diabetic Hearts Attenuates Myocardial Ischemia/Reperfusion Injury via Mitochondria Apoptosis Pathway.
复制标题
抑制糖尿病心脏中过度的组蛋白脱乙酰酶活性可通过线粒体凋亡途径减轻心肌缺血/再灌注损伤
DOI：
10.1155/2017/8208065
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发表时间：
2017
影响因子：
4.3
通讯作者：
Xia Z
中科院分区：
文献类型：
--
作者：
Wu Y;Leng Y;Meng Q;Xue R;Zhao B;Zhan L;Xia Z
背景资料。组蛋白脱乙酰酶(HDAC)在心血管病理生理学所必需的信号修饰和基因转录调控中起着关键作用。与非糖尿病心脏相比，HDACs活性高的糖尿病心脏更容易受到心肌缺血/再灌注(MI/R)损伤。我们好奇的是，抑制糖尿病心脏中过度的HDACs活性是否能保护心肌免受MI/R损伤。方法：研究方法。糖尿病大鼠缺血45 ，再灌流3 h。H9C2心肌细胞暴露于高糖24 h，然后是低氧4 h和复氧2 h。结果。MI/R损伤和糖尿病均使心肌HDACs活性升高。经HDACs抑制剂曲古抑素A(TSA)治疗的糖尿病大鼠，MI/R诱导的细胞凋亡明显减少。TSA可明显减缓线粒体膜电位的耗散，保护线粒体膜通透性转换孔(MPTP)的完整性，减少细胞凋亡。值得注意的是，与Akt抑制剂共同处理部分或完全抑制了TSA在体内和体外的保护作用。此外，TSA可激活Akt/Foxo3a途径，导致Foxo3a细胞质易位，抑制促凋亡蛋白Bim的表达。结论。糖尿病和MI/R损伤均使心肌HDACs活性升高。抑制HDACs活性可通过Akt通过Foxo3a/Bim调节线粒体的凋亡途径，从而对高血糖条件下的MI/R和H/R损伤产生保护作用。
Background. Histone deacetylases (HDACs) play a pivotal role in signaling modification and gene transcriptional regulation that are essential for cardiovascular pathophysiology. Diabetic hearts with higher HDACs activity were more vulnerable to myocardial ischemia/reperfusion (MI/R) injury compared with nondiabetic hearts. We are curious about whether suppression of excessive HDACs activity in diabetic heart protects against MI/R injury. Methods. Diabetic rats were subjected to 45 min of ischemia, followed by 3 h of reperfusion. H9C2 cardiomyocytes were exposed to high glucose for 24 h, followed by 4 h of hypoxia and 2 h of reoxygenation (H/R). Results. Both MI/R injury and diabetes mellitus elevated myocardium HDACs activity. MI/R induced apoptotic cell death was significantly decreased in diabetic rats treated with HDACs inhibitor trichostatin A (TSA). TSA administration markedly moderated dissipation of mitochondrial membrane potential, protected the integrity of mitochondrial permeability transition pore (mPTP), and decreased cell apoptosis. Notably, cotreatment with Akt inhibitor partly or absolutely inhibited the protective effect of TSA in vivo and in vitro. Furthermore, TSA administration activated Akt/Foxo3a pathway, leading to Foxo3a cytoplasm translocation and attenuation proapoptosis protein Bim expression. Conclusions. Both diabetes mellitus and MI/R injury increased cardiac HDACs activity. Suppression of HDACs activity triggered protective effects against MI/R and H/R injury under hyperglycemia conditions through Akt-modulated mitochondrial apoptotic pathways via Foxo3a/Bim.