Department of Cardiology and Hypertension, Jilin Provincial Key Laboratory of Stress and Cardiovascular Disease, Yanbian University Hospital, Yanji, Jilin, China.
Department of Cardiology, The Wuxi Fifth People's Hospital, The Fifth Affiliated Hospital of Jiangnan University, Wuxi, Jiangshu, China.
J Cell Mol Med. 2024 Sep;28(17):e70063. doi: 10.1111/jcmm.70063.
Histone deacetylase 6 (HDAC6) belongs to the class IIb group of the histone deacetylase family, which participates in remodelling of various tissues. Herein, we sought to examine the potential regulation of HDAC6 in cardiac remodelling post-infarction. Experimental myocardial infarction (MI) was created in HDAC6-deficient (HDAC6) mice and wild-type (HADC6) by left coronary artery ligation. At days 0 and 14 post-MI, we evaluated cardiac function, morphology and molecular endpoints of repair and remodelling. At day 14 after surgery, the ischemic myocardium had increased levels of HADC6 gene and protein of post-MI mice compared to the non-ischemic myocardium of control mice. As compared with HDAC6-MI mice, HADC6 deletion markedly improved infarct size and cardiac fibrosis as well as impaired left ventricular ejection fraction and left ventricular fraction shortening. At the molecular levels, HDAC6 resulted in a significant reduction in the levels of the transforming growth factor-beta 1 (TGF-β1), phosphor-Smad-2/3, collagen I and collagen III proteins and/or in the ischemic cardiac tissues. All of these beneficial effects were reproduced by a pharmacological inhibition of HADC6 in vivo. In vitro, hypoxic stress increased the expressions of HADC6 and collagen I and III gene; these alterations were significantly prevented by the HADC6 silencing and TubA loading. These findings indicated that HADC6 deficiency resists ischemic injury by a reduction of TGF-β1/Smad2/3 signalling activation, leading to decreased extracellular matrix production, which reduces cardiac fibrosis and dysfunction, providing a potential molecular target in the treatment of patients with MI.
组蛋白去乙酰化酶 6（HDAC6）属于组蛋白去乙酰化酶家族的 IIb 类，参与多种组织的重塑。在此，我们试图研究 HDAC6 在心肌梗死后心脏重塑中的潜在调节作用。通过左冠状动脉结扎，在 HDAC6 缺陷（HDAC6）小鼠和野生型（HADC6）小鼠中创建实验性心肌梗死（MI）。在 MI 后第 0 天和第 14 天，我们评估了心脏功能、形态以及修复和重塑的分子终点。在手术后第 14 天，与对照组非缺血心肌相比，缺血心肌中 MI 后小鼠的 HDAC6 基因和蛋白水平升高。与 HDAC6-MI 小鼠相比，HDAC6 缺失明显改善了梗死面积和心脏纤维化，同时损害了左心室射血分数和左心室缩短分数。在分子水平上，HDAC6 导致转化生长因子-β1（TGF-β1）、磷酸化 Smad-2/3、胶原 I 和胶原 III 蛋白水平显著降低，并且/或者在缺血性心脏组织中降低。在体内，HDAC6 的药理学抑制重现了所有这些有益作用。在体外，缺氧应激增加了 HDAC6 和胶原 I 和 III 基因的表达；这些变化通过 HDAC6 沉默和 TubA 加载得到显著预防。这些发现表明，HDAC6 缺失通过减少 TGF-β1/Smad2/3 信号激活来抵抗缺血损伤，导致细胞外基质产生减少，从而减少心脏纤维化和功能障碍，为 MI 患者的治疗提供了一个潜在的分子靶点。
