Department of Emergency Medicine, Department of Medicine, Rhode Island Hospital, Brown University, Providence, RI, USA.
Department of Surgery, Boston University Medical School, Roger Williams Medical Center, 50 Maude Street, Providence, RI, 02908, USA.
Mol Med. 2018 Jul 17;24(1):37. doi: 10.1186/s10020-018-0037-2.
Histone deacetylases (HDACs) play a critical role in modulating myocardial protection and cardiomyocyte survivals. However, Specific HDAC isoforms in mediating myocardial ischemia/reperfusion injury remain currently unknown. We used cardiomyocyte-specific overexpression of active HDAC4 to determine the functional role of activated HDAC4 in regulating myocardial ischemia and reperfusion in isovolumetric perfused hearts.
In this study, we created myocyte-specific active HDAC4 transgenic mice to examine the functional role of active HDAC4 in mediating myocardial I/R injury. Ventricular function was determined in the isovolumetric heart, and infarct size was determined using tetrazolium chloride staining.
Myocyte-specific overexpressing activated HDAC4 in mice promoted myocardial I/R injury, as indicated by the increases in infarct size and reduction of ventricular functional recovery following I/R injury. Notably, active HDAC4 overexpression led to an increase in LC-3 and active caspase 3 and decrease in SOD-1 in myocardium. Delivery of chemical HDAC inhibitor attenuated the detrimental effects of active HDAC4 on I/R injury, revealing the pivotal role of active HDAC4 in response to myocardial I/R injury.
Taken together, these findings are the first to define that activated HDAC4 as a crucial regulator for myocardial ischemia and reperfusion injury.
组蛋白去乙酰化酶（HDACs）在调节心肌保护和心肌细胞存活方面起着至关重要的作用。然而，目前尚不清楚介导心肌缺血/再灌注损伤的特定 HDAC 同工酶。我们使用心肌细胞特异性过表达活性 HDAC4 来确定激活的 HDAC4 在调节等容灌流心脏中的心肌缺血和再灌注中的功能作用。
在这项研究中，我们创建了心肌细胞特异性过表达活性 HDAC4 的转基因小鼠，以研究活性 HDAC4 在介导心肌 I/R 损伤中的功能作用。在等容心脏中测定心室功能，并使用氯化四唑染色测定梗死面积。
心肌细胞特异性过表达激活的 HDAC4 可促进心肌 I/R 损伤，表现为 I/R 损伤后梗死面积增加和心室功能恢复减少。值得注意的是，活性 HDAC4 过表达导致心肌中 LC-3 和活性 caspase 3 增加，SOD-1 减少。化学 HDAC 抑制剂的传递减轻了活性 HDAC4 对 I/R 损伤的有害影响，揭示了活性 HDAC4 在应对心肌 I/R 损伤中的关键作用。
综上所述，这些发现首次定义了激活的 HDAC4 是心肌缺血和再灌注损伤的关键调节因子。
