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Abstract Background 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. Methods 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. Results 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. Conclusions Taken together, these findings are the first to define that activated HDAC4 as a crucial regulator for myocardial ischemia and reperfusion injury.

Abstract: Thrombomodulin (TM) is an important vascular protective molecule that has anticoagulant, anti-inflammatory and anti-apoptotic properties. TM is downregulated in many thrombotic and vascular diseases. However, the mechanisms responsible for TM suppression are not completely understood. In this study, we investigated the mechanism involved in fatty acid-induced suppression of TM expression in human aortic endothelial cells. We found that palmitic acid inhibited TM expression through the JNK and p38 pathways. ATF-2, a JNK and p38 target transcription factor, was involved in the suppression. ATF-2 can bind to the TM promoter, recruit HDAC4 and form a transcriptional repression complex in the promoter, which may lead to chromatin condensation and transcriptional arrest. This study provides novel insight into TM down-regulation by stress signaling pathways. Structured summary: MINT-7555703, MINT-7555712: HDAC4 (uniprotkb:P56524) physically interacts (MI:0915) with ATF-2 (uniprotkb:P15336) by anti bait coimmunoprecipitation (MI:0006) [Copyright &y& Elsevier]