Histone deacetylase (HDAC) inhibition improves myocardial function and prevents cardiac remodeling in diabetic mice

被引:136
作者
Chen, Youfang [1 ]
Du, Jianfeng [1 ]
Zhao, Yu Tina [1 ]
Zhang, Ling [2 ]
Lv, Guorong [3 ]
Zhuang, Shougang [2 ]
Qin, Gangjian [4 ]
Zhao, Ting C. [1 ]
机构
[1] Boston Univ, Dept Surg, Sch Med, Roger Williams Med Ctr, Providence, RI 02908 USA
[2] Brown Univ, Rhode Isl Hosp, Dept Med, Providence, RI 02903 USA
[3] Fujian Med Univ, Affiliated Hosp 2, Dept Ultrasound, Quanzhou, Fujian, Peoples R China
[4] Northwestern Univ, Sch Med, Feinberg Cardiovasc Res Inst, Chicago, IL 60611 USA
关键词
HDAC; Diabetes; Myocardium; Heart failure; Apoptosis; GLUT; GLUCAGON-LIKE PEPTIDE-1; MITOCHONDRIAL RESPIRATION; REPERFUSION INJURY; HEART; MOUSE; CARDIOMYOPATHY; CARDIOPROTECTION; ANGIOGENESIS; HYPERTROPHY; EPIGENETICS;
D O I
10.1186/s12933-015-0262-8
中图分类号
R5 [内科学];
学科分类号
100201 [内科学];
摘要
Background: 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. Methods: 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. Results: 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. Conclusion: HDAC inhibition plays a critical role in improving cardiac function and suppressing myocardial remodeling in diabetic heart.
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页数:13
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