Baumgardt Shelley L, Fang Juan, Fu Xuebin, Liu Yanan, Xia Zhengyuan, Zhao Ming, Chen Ling, Mishra Rachana, Gunasekaran Muthukumar, Saha Progyaparamita, Forbess Joseph M, Bosnjak Zeljko J, Camara Amadou Ks, Kersten Judy R, Thorp Edward, Kaushal Sunjay, Ge Zhi-Dong
Departments of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206.
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53206.
bioRxiv. 2023 Feb 22:2023.02.21.529462. doi: 10.1101/2023.02.21.529462.
Diabetes augments activity of histone deacetylase 6 (HDAC6) and generation of tumor necrosis factor α (TNFα) and impairs the physiological function of mitochondrial complex I (mCI) which oxidizes reduced nicotinamide adenine dinucleotide (NADH) to nicotinamide adenine dinucleotide to sustain the tricarboxylic acid cycle and β-oxidation. Here we examined how HDAC6 regulates TNFα production, mCI activity, mitochondrial morphology and NADH levels, and cardiac function in ischemic/reperfused diabetic hearts.
HDAC6 knockout, streptozotocin-induced type 1 diabetic, and obese type 2 diabetic db/db mice underwent myocardial ischemia/reperfusion injury or in a Langendorff-perfused system. H9c2 cardiomyocytes with and without HDAC6 knockdown were subjected to hypoxia/reoxygenation injury in the presence of high glucose. We compared the activities of HDAC6 and mCI, TNFα and mitochondrial NADH levels, mitochondrial morphology, myocardial infarct size, and cardiac function between groups.
Myocardial ischemia/reperfusion injury and diabetes synergistically augmented myocardial HDCA6 activity, myocardial TNFα levels, and mitochondrial fission and inhibited mCI activity. Interestingly, neutralization of TNFα with an anti-TNFα monoclonal antibody augmented myocardial mCI activity. Importantly, genetic disruption or inhibition of HDAC6 with 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 ameliorated cardiac dysfunction. In H9c2 cardiomyocytes cultured in high glucose, hypoxia/reoxygenation augmented HDAC6 activity and TNFα levels and decreased mCI activity. These negative effects were blocked by HDAC6 knockdown.
Augmenting HDAC6 activity inhibits mCI activity by increasing TNFα levels in ischemic/reperfused diabetic hearts. The HDAC6 inhibitor, tubastatin A, has high therapeutic potential for acute myocardial infarction in diabetes.
糖尿病会增强组蛋白去乙酰化酶6（HDAC6）的活性以及肿瘤坏死因子α（TNFα）的生成，并损害线粒体复合物I（mCI）的生理功能，该复合物将还原型烟酰胺腺嘌呤二核苷酸（NADH）氧化为烟酰胺腺嘌呤二核苷酸以维持三羧酸循环和β-氧化。在此，我们研究了HDAC6如何调节TNFα的产生、mCI活性、线粒体形态和NADH水平以及缺血/再灌注糖尿病心脏的心脏功能。
对HDAC6基因敲除小鼠、链脲佐菌素诱导的1型糖尿病小鼠和肥胖2型糖尿病db/db小鼠进行心肌缺血/再灌注损伤，或在Langendorff灌注系统中进行相关实验。对有或没有HDAC6基因敲低的H9c2心肌细胞在高糖存在的情况下进行缺氧/复氧损伤。我们比较了各组之间HDAC6和mCI的活性、TNFα和线粒体NADH水平、线粒体形态、心肌梗死面积和心脏功能。
心肌缺血/再灌注损伤和糖尿病协同增强心肌HDCA6活性、心肌TNFα水平以及线粒体分裂，并抑制mCI活性。有趣的是，用抗TNFα单克隆抗体中和TNFα可增强心肌mCI活性。重要的是，用tubastatin A对HDAC6进行基因破坏或抑制可降低缺血/再灌注糖尿病小鼠的TNFα水平、线粒体分裂和心肌线粒体NADH水平，同时增强mCI活性、减小梗死面积并改善心脏功能障碍。在高糖培养的H9c2心肌细胞中，缺氧/复氧会增强HDAC6活性和TNFα水平，并降低mCI活性。这些负面影响可通过HDAC6基因敲低来阻断。
在缺血/再灌注糖尿病心脏中，增强HDAC6活性会通过增加TNFα水平来抑制mCI活性。HDAC6抑制剂tubastatin A对糖尿病急性心肌梗死具有很高的治疗潜力。
