Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.
Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice.
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DOI：
10.1186/s12933-015-0262-8
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发表时间：
2015-08-07
影响因子：
9.3
通讯作者：
Zhao TC
中科院分区：
文献类型：
--
作者：
Chen Y;Du J;Zhao YT;Zhang L;Lv G;Zhuang S;Qin G;Zhao TC
最近的证据表明，抑制组蛋白去乙酰化酶（HDAC）保护心脏免受心肌损伤，并刺激内源性血管肌生成。然而，HDAC抑制是否在糖尿病心脏中产生保护作用仍然未知。我们试图确定HDAC抑制是否能保护糖尿病心肌病患者的心脏功能并抑制心脏重塑。成年ICR小鼠腹腔注射链脲佐菌素（STZ，200 mg/kg）建立糖尿病模型，或注射溶剂作为对照。一旦确认高血糖，糖尿病小鼠每天在饮用水中接受丁酸钠（1%），一种特异性HDAC抑制剂，以抑制HDAC活性。将小鼠随机分为对照组、对照组+丁酸钠组、STZ组和STZ +丁酸钠组。分别于治疗后7、14、21周对心肌功能进行动态观察。超声心动图显示，糖尿病小鼠的心脏功能受到抑制，但HDAC抑制导致STZ注射小鼠的功能显着改善。同样地，HDAC抑制减弱心脏肥大，如通过减少的心脏/胫骨比和心肌细胞面积所证明的，这与减少的间质纤维化和活性半胱天冬酶-3和凋亡染色的减少有关，而且还增加了糖尿病心肌中的血管生成。值得注意的是，葡萄糖转运蛋白（GLUT）1和4在HDAC抑制后上调，这伴随着GLUT 1乙酰化和p38磷酸化的增加。此外，心肌超氧化物歧化酶，一个重要的抗氧化剂，升高后HDAC抑制糖尿病小鼠。HDAC抑制在改善糖尿病心脏的心功能和抑制心肌重构中起关键作用。本文的在线版本（doi：10.1186/s12933-015-0262-8）包含补充材料，可供授权用户使用。
Recent evidence indicates that inhibition of histone deacetylase (HDAC) protects the heart against myocardial injury and stimulates endogenous angiomyogenesis. However, it remains unknown whether HDAC inhibition produces the protective effect in the diabetic heart. We sought to determine whether HDAC inhibition preserves cardiac performance and suppresses cardiac remodeling in diabetic cardiomyopathy. Adult ICR mice received an intraperitoneal injection of either streptozotocin (STZ, 200 mg/kg) to establish the diabetic model or vehicle to serve as control. Once hyperglycemia was confirmed, diabetic mice received sodium butyrate (1%), a specific HDAC inhibitor, in drinking water on a daily basis to inhibit HDAC activity. Mice were randomly divided into following groups, which includes Control, Control + Sodium butyrate (NaBu), STZ and STZ + Sodium butyrate (NaBu), respectively. Myocardial function was serially assessed at 7, 14, 21 weeks following treatments. Echocardiography demonstrated that cardiac function was depressed in diabetic mice, but HDAC inhibition resulted in a significant functional improvement in STZ-injected mice. Likewise, HDAC inhibition attenuates cardiac hypertrophy, as evidenced by a reduced heart/tibia ratio and areas of cardiomyocytes, which is associated with reduced interstitial fibrosis and decreases in active caspase-3 and apoptotic stainings, but also increased angiogenesis in diabetic myocardium. Notably, glucose transporters (GLUT) 1 and 4 were up-regulated following HDAC inhibition, which was accompanied with increases of GLUT1 acetylation and p38 phosphorylation. Furthermore, myocardial superoxide dismutase, an important antioxidant, was elevated following HDAC inhibition in the diabetic mice. HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart. The online version of this article (doi:10.1186/s12933-015-0262-8) contains supplementary material, which is available to authorized users.