Department of Anesthesiology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA.
Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53206, USA.
Cardiovasc Res. 2024 Oct 14;120(12):1456-1471. doi: 10.1093/cvr/cvae144.
The histone deacetylase 6 (HDAC6) inhibitor, tubastatin A (TubA), reduces myocardial ischaemia/reperfusion injury (MIRI) in type 1 diabetic rats. It remains unclear whether HDAC6 regulates MIRI in type 2 diabetic animals. Diabetes augments the activity of HDAC6 and the generation of tumour necrosis factor alpha (TNF-α) and impairs mitochondrial complex I (mCI). Here, we examined how HDAC6 regulates TNF-α 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 TNF-α, along with cardiac mitochondrial fission, low bioactivity of mCI, and low production of adenosine triphosphate. Importantly, genetic disruption of HDAC6 or TubA decreased TNF-α levels, mitochondrial fission, and myocardial mitochondrial nicotinamide adenine dinucleotide levels in ischaemic/reperfused diabetic mice, concomitant with augmented mCI activity, decreased infarct size, and improved cardiac function. Moreover, HDAC6 knockout or TubA 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 TNF-α 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 TNF-α-induced mitochondrial injury in experimental diabetes.
组蛋白去乙酰化酶 6（HDAC6）抑制剂 tubastatin A（TubA）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。糖尿病会增加 HDAC6 的活性和肿瘤坏死因子-α（TNF-α）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 1 型和 2 型糖尿病小鼠 MIRI 中的 TNF-α 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 小鼠在 Langendorff 灌注系统中进行体内或离体 MIRI。我们发现，MIRI 和糖尿病可累加增加心肌 HDAC6 活性和 TNF-α的产生，同时伴有心脏线粒体裂变、mCI 生物活性降低和三磷酸腺苷产生减少。重要的是，HDAC6 的基因敲除或 TubA 降低了缺血/再灌注糖尿病小鼠的 TNF-α水平、线粒体裂变和心肌烟酰胺腺嘌呤二核苷酸水平，同时增加了 mCI 活性、减少了梗死面积并改善了心脏功能。此外，HDAC6 敲除或 TubA 治疗可减少 MIRI 后 28 天的左心室扩张并改善心脏收缩功能。在高葡萄糖存在的情况下，用和不用 HDAC6 敲低的 H9c2 心肌细胞进行缺氧/复氧损伤。缺氧/复氧增加了 HDAC6 的活性和 TNF-α的水平，降低了 mCI 的活性。这些负面影响被 HDAC6 敲低所阻断。
HDAC6 是糖尿病中 MIRI 的一个重要的负调节因子。HDAC6 的基因缺失或药理学抑制通过限制 TNF-α 诱导的线粒体损伤来保护心脏免受实验性糖尿病的 MIRI。
