Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China.
Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei Province 430060, China.
J Diabetes Res. 2019 Feb 13;2019:8520856. doi: 10.1155/2019/8520856. eCollection 2019.
A substantial increase in histone deacetylase 3 (HDAC3) expression is implicated in the pathological process of diabetes and stroke. However, it is unclear whether HDAC3 plays an important role in diabetes complicated with stroke. We aimed to explore the role and the potential mechanisms of HDAC3 in cerebral ischemia/reperfusion (I/R) injury in diabetic state.
Diabetic mice were subjected to 1 h ischemia, followed by 24 h reperfusion. PC12 cells were exposed to high glucose for 24 h, followed by 3 h of hypoxia and 6 h of reoxygenation (H/R). Diabetic mice received RGFP966 (the specific HDAC3 inhibitor) or vehicle 30 minutes before the middle cerebral artery occlusion (MCAO), and high glucose-incubated PC12 cells were pretreated with RGFP966 or vehicle 6 h before H/R.
HDAC3 inhibition reduced the cerebral infarct volume, ameliorated pathological changes, improved the cell viability and cytotoxicity, alleviated apoptosis, attenuated oxidative stress, and enhanced autophagy in cerebral I/R injury model in diabetic state in vivo and in vitro. Furthermore, we found that the expression of HDAC3 was remarkably amplified, and the Bmal1 expression was notably decreased in diabetic mice with cerebral I/R, whereas this phenomenon was obviously reversed by RGFP966 pretreatment.
These results suggested that the HDAC3 was involved in the pathological process of the complex disease of diabetic stroke. Suppression of HDAC3 exerted protective effects against cerebral I/R injury in diabetic state in vivo and in vitro via the modulation of oxidative stress, apoptosis, and autophagy, which might be mediated by the upregulation of Bmal1.
组蛋白去乙酰化酶 3（HDAC3）表达的大量增加与糖尿病和中风的病理过程有关。然而，HDAC3 是否在糖尿病并发中风中发挥重要作用尚不清楚。我们旨在探讨 HDAC3 在糖尿病状态下脑缺血/再灌注（I/R）损伤中的作用及其潜在机制。
糖尿病小鼠接受 1 小时缺血，随后进行 24 小时再灌注。PC12 细胞在高葡萄糖中孵育 24 小时，然后进行 3 小时缺氧和 6 小时复氧（H/R）。糖尿病小鼠在大脑中动脉闭塞（MCAO）前 30 分钟接受 RGFP966（特异性 HDAC3 抑制剂）或载体，高葡萄糖孵育的 PC12 细胞在 H/R 前 6 小时用 RGFP966 或载体预处理。
HDAC3 抑制减少了脑梗死体积，改善了病理变化，提高了细胞活力和细胞毒性，减轻了细胞凋亡，减轻了氧化应激，增强了糖尿病状态下体内和体外脑 I/R 损伤模型中的自噬。此外，我们发现 HDAC3 的表达在糖尿病伴脑 I/R 的小鼠中明显放大，Bmal1 的表达明显降低，而 RGFP966 预处理明显逆转了这种现象。
这些结果表明，HDAC3 参与了糖尿病性中风这一复杂疾病的病理过程。在体内和体外，抑制 HDAC3 通过调节氧化应激、细胞凋亡和自噬，对糖尿病状态下的脑 I/R 损伤发挥保护作用，这可能是通过上调 Bmal1 介导的。
