Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan 430060, PR China.
J Mol Cell Cardiol. 2019 Mar;128:160-178. doi: 10.1016/j.yjmcc.2019.01.027. Epub 2019 Jan 31.
High mobility group protein AT-hook 2 (HMGA2), an architectural transcription factor, has previously been reported to play an essential role in regulating the expression of many genes through architectural remodeling processes. However, the effects of HMGA2 on cardiovascular disease, especial cardiac remodeling, is unclear. This study was aimed at investigating the functional role of HMGA2 in pressure overload-induced cardiac remodeling. Mice that were subjected to aortic banding (AB) for 8 weeks developed myocardial hypertrophy and cardiac dysfunction, which were associated with altered expression of HMGA2. Cardiac-specific expression of the human HMGA2 gene in mice with an adeno-related virus 9 delivery system ameliorated cardiac remodeling and improve cardiac function in response to pressure overload by activating PPARγ/NRF2 signaling. Knockdown of HMGA2 by AAV9-shHMGA2 accelerated cardiac remodeling after 1 weeks of AB surgery. Additionally, knockdown of heart PPARγ largely abolished HMGA2 overexpression-mediated cardioprotection. HMGA2-mediated cardiomyocyte protection was largely abrogated by knocking down NRF2 and inhibiting PPARγ in cardiomyocytes. PPARγ activation was mediated by C/EBPβ, which directly interacted with HMGA2. Knocking down C/EBPβ offset the effects of HMGA2 on PPARγ activation and cardioprotection. These findings show that the overexpression of HMGA2 ameliorates the remodeling response to pressure overload, and they also imply that the upregulation of HMGA2 may become a treatment strategy in cardiac pathologies.
高迁移率族蛋白 A2（HMGA2）是一种结构转录因子，先前已有报道称其通过结构重塑过程在调节许多基因的表达中发挥重要作用。然而，HMGA2 对心血管疾病，特别是心脏重塑的影响尚不清楚。本研究旨在探讨 HMGA2 在压力超负荷诱导的心脏重塑中的功能作用。用主动脉缩窄（AB）处理 8 周的小鼠发生心肌肥厚和心脏功能障碍，这与 HMGA2 的表达改变有关。通过腺相关病毒 9 传递系统在小鼠中特异性表达人 HMGA2 基因，通过激活 PPARγ/NRF2 信号改善了心脏重塑并改善了对压力超负荷的心脏功能。在 AB 手术后 1 周，用 AAV9-shHMGA2 敲低 HMGA2 加速了心脏重塑。此外，心脏 PPARγ 的敲低大大消除了 HMGA2 过表达介导的心脏保护作用。在心肌细胞中敲低 NRF2 和抑制 PPARγ 大大消除了 HMGA2 介导的心肌细胞保护作用。PPARγ 的激活是由 C/EBPβ介导的，C/EBPβ 与 HMGA2 直接相互作用。敲低 C/EBPβ 抵消了 HMGA2 对 PPARγ 激活和心脏保护的影响。这些发现表明，HMGA2 的过表达可改善对压力超负荷的重塑反应，并且暗示 HMGA2 的上调可能成为心脏病理学的一种治疗策略。
