Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke.
Inhibiting Histone Deacetylase 2 (HDAC2) Promotes Functional Recovery From Stroke.
复制标题
抑制组蛋白脱乙酰酶 2 (HDAC2) 可促进中风功能恢复
DOI：
10.1161/jaha.117.007236
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发表时间：
2017-10-05
影响因子：
5.4
通讯作者：
Zhu DY
中科院分区：
文献类型：
--
作者：
Tang Y;Lin YH;Ni HY;Dong J;Yuan HJ;Zhang Y;Liang HY;Yao MC;Zhou QG;Wu HY;Chang L;Luo CX;Zhu DY
中风是全球长期残疾的主要原因。然而，目前促进中风功能恢复的疗法仅限于身体康复。无可用的药物治疗。因此，了解组蛋白去乙酰化酶2（HDAC 2）在卒中诱导的功能丧失的病理生理过程中的作用可能为卒中恢复提供新的策略。局灶性卒中由光血栓形成诱导。中风后立即将LV-HDAC 2-shRNA-GFP、LV-GFP、Ad-HDAC 2-Flag或Ad-失活-HDAC 2-Flag显微注射到脑梗死区域。在中风后4至10天将HDAC抑制剂微量注射到脑梗死区域。进行网格行走任务和圆柱任务以评估运动功能。高尔基考克斯染色，染色质免疫沉淀和电生理学被用来揭示中风恢复的机制。HDAC 2的敲低或敲除促进卒中恢复，而HDAC 2的过表达使卒中诱导的功能障碍恶化。更重要的是，当在延迟期使用时，泛HDAC抑制剂阿司他汀A促进WT小鼠中风的功能恢复，但在Hdac 2条件性敲除（Hdac 2 CKO）小鼠中无效。在中风的延迟期使用辛二酰苯胺异羟肟酸（一种选择性HDAC 1和HDAC 2抑制剂）治疗，通过表观遗传学增强脑梗死区存活神经元的神经可塑性，使小鼠的功能持续恢复。我们的新发现提供了HDAC 2是中风功能恢复的关键靶点的证据。由于临床上已有HDAC抑制剂，我们的研究结果可以直接转化为中风的临床研究。
Stroke is a leading cause of long‐term disability worldwide. However, current therapies that promote functional recovery from stroke are limited to physical rehabilitation. No pharmacological therapy is available. Thus, understanding the role of histone deacetylase 2 (HDAC2) in the pathophysiological process of stroke‐induced functional loss may provide a novel strategy for stroke recovery. Focal stroke was induced by photothrombosis. LV‐HDAC2‐shRNA‐GFP, LV‐GFP, Ad‐HDAC2‐Flag, or Ad‐inactive‐HDAC2‐Flag was microinjected into the peri‐infarct area immediately after stroke. HDAC inhibitors were microinjected into the peri‐infarct area 4 to 10 days after stroke. Grid‐walking task and cylinder task were conducted to assess motor function. Golgi‐Cox staining, chromatin immunoprecipitation, and electrophysiology were used to reveal the mechanisms underlying stroke recovery. Knockdown or knockout of HDAC2 promoted stroke recovery, whereas overexpression of HDAC2 worsened stroke‐induced functional impairment. More importantly, trichostatin A, a pan‐HDAC inhibitor, promoted functional recovery from stroke in WT mice when used in the delayed phase, but it was ineffective in Hdac2 conditional knockout (Hdac2 CKO) mice. Treatment with suberoylanilide hydroxamic acid, a selective HDAC1 and HDAC2 inhibitor, in the delayed phase of stroke produced sustained functional recovery in mice via epigenetically enhancing neuroplasticity of surviving neurons in the peri‐infarct zone. Our novel findings provide evidence that HDAC2 is a crucial target for functional recovery from stroke. As there are clinically available HDAC inhibitors, our findings could be directly translated into clinical research of stroke.