Abstract：
OBJECTIVE: The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A, reduces myocardial ischemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments activity of HDAC6 and generation of tumor necrosis factor α (TNFα) and impairs mitochondrial complex I (mCI). Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondria, and cardiac function in type 1 and type 2 diabetic mice undergoing MIRI.
RESULTS: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNFα, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of ATP. Importantly, genetic disruption of HDAC6 or tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or tubastatin A treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.
CONCLUSIONS: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNFα-induced mitochondrial injury in experimental diabetes.
RESULTS: HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent MIRI in vivo or ex vivo in a Langendorff-perfused system. We found that MIRI and diabetes additively augmented myocardial HDAC6 activity and generation of TNFα, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of ATP. Importantly, genetic disruption of HDAC6 or tubastatin A decreased TNFα levels, mitochondrial fission, and myocardial mitochondrial NADH levels in ischemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or tubastatin A treatment decreased left ventricular dilation and improved cardiac systolic function 28 days after MIRI. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. Hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.
CONCLUSIONS: HDAC6 is an essential negative regulator of MIRI in diabetes. Genetic deletion or pharmacologic inhibition of HDAC6 protects the heart from MIRI by limiting TNFα-induced mitochondrial injury in experimental diabetes.
摘要：
目的：组蛋白去乙酰化酶6（HDAC6）抑制剂，妥司他丁A,减轻1型糖尿病大鼠心肌缺血/再灌注损伤(MIRI)。尚不清楚HDAC6是否在2型糖尿病动物中调节MIRI。糖尿病增加HDAC6的活性和肿瘤坏死因子α（TNFα）的产生，并损害线粒体复合物I（mCI）。在这里，我们研究了HDAC6如何调节TNFα的产生，MCI活动,线粒体,接受MIRI的1型和2型糖尿病小鼠的心功能。
结果：HDAC6敲除，链脲佐菌素诱导的1型糖尿病，肥胖的2型糖尿病db/db小鼠在Langendorff灌注系统中进行了体内或离体MIRI。我们发现MIRI和糖尿病会增加心肌HDAC6活性和TNFα的产生，伴随着心脏线粒体裂变，MCI的生物活性低，ATP产量低。重要的是,HDAC6或替他汀A的遗传破坏降低了TNFα水平，线粒体裂变,缺血/再灌注糖尿病小鼠的心肌线粒体NADH水平，伴随着MCI活动的增强，梗死面积减小，和改善心脏功能。此外，HDAC6敲除或替他汀A治疗减少了MIRI后28天的左心室扩张并改善了心脏收缩功能。在高葡萄糖存在下,对具有和不具有HDAC6敲除的H9c2心肌细胞进行缺氧/复氧损伤。缺氧/复氧会增加HDAC6活性和TNFα水平，并降低mCI活性。这些负面影响被HDAC6敲低阻断。
结论：HDAC6是糖尿病患者MIRI的重要负调节因子。HDAC6的遗传缺失或药理学抑制通过限制实验性糖尿病中TNFα诱导的线粒体损伤来保护心脏免受MIRI。
结果：HDAC6敲除，链脲佐菌素诱导的1型糖尿病，肥胖的2型糖尿病db/db小鼠在Langendorff灌注系统中进行了体内或离体MIRI。我们发现MIRI和糖尿病会增加心肌HDAC6活性和TNFα的产生，伴随着心脏线粒体裂变，MCI的生物活性低，ATP产量低。重要的是,HDAC6或替他汀A的遗传破坏降低了TNFα水平，线粒体裂变,缺血/再灌注糖尿病小鼠的心肌线粒体NADH水平，伴随着MCI活动的增强，梗死面积减小，和改善心脏功能。此外，HDAC6敲除或替他汀A治疗减少了MIRI后28天的左心室扩张并改善了心脏收缩功能。在高葡萄糖存在下,对具有和不具有HDAC6敲除的H9c2心肌细胞进行缺氧/复氧损伤。缺氧/复氧会增加HDAC6活性和TNFα水平，并降低mCI活性。这些负面影响被HDAC6敲低阻断。
结论：HDAC6是糖尿病患者MIRI的重要负调节因子。HDAC6的遗传缺失或药理学抑制通过限制实验性糖尿病中TNFα诱导的线粒体损伤来保护心脏免受MIRI。
