组蛋白脱乙酰酶 6 (HDAC6) 抑制剂 Tustatatin A 可减轻 1 型糖尿病大鼠的心肌缺血/再灌注损伤 (MIRI)。目前尚不清楚 HDAC6 是否调节 2 型糖尿病动物的 MIRI。糖尿病会增强 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 如何调节接受 MIRI 的 1 型和 2 型糖尿病小鼠中的 TNFα 产生、mCI 活性、线粒体和心脏功能。HDAC6 敲除、链脲佐菌素诱导的 1 型糖尿病和肥胖 2 型糖尿病 db/db 小鼠接受 MIRI Langendorff 灌注系统中的体内或离体。我们发现 MIRI 和糖尿病会增加心肌 HDAC6 活性和 TNFα 的产生，同时还会增加心肌线粒体裂变、mCI 生物活性低和 ATP 产生低。重要的是，HDAC6 或图巴他汀 A 的基因破坏降低了缺血/再灌注糖尿病小鼠的 TNFα 水平、线粒体裂变和心肌线粒体 NADH 水平，同时增强了 mCI 活性、减小了梗塞面积并改善了心脏功能。此外，MIRI 后 28 天，HDAC6 敲除或图巴他汀 A 治疗可减少左心室扩张并改善心脏收缩功能。敲低和未敲除 HDAC6 的 H9c2 心肌细胞在高葡萄糖存在下遭受缺氧/复氧损伤。缺氧/复氧增强了 HDAC6 活性和 TNFα 水平，并降低了 mCI 活性。这些负面影响可通过 HDAC6 敲除来阻断。HDAC6 是糖尿病中 MIRI 的重要负调节因子。 HDAC6 的基因缺失或药物抑制可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 的影响。© 作者 2024。由牛津大学出版社代表欧洲心脏病学会出版。版权所有。如需商业重复使用，请联系 reprints@oup.com 获取转载和转载的翻译权。所有其他权限都可以通过我们网站文章页面上的权限链接通过我们的 RightsLink 服务获得 - 如需了解更多信息，请联系journals.permissions@oup.com。

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.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.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.© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.