Sympathetic stimulated-cardiac fibrosis imposes great significance on both disease progression and survival in the pathogenesis of many cardiovascular diseases. However, there are few effective therapies targeting it clinically. The cardioprotective effect of aldehyde dehydrogenase 2 (ALDH2) has been explored in many pathological conditions, whether it can exert benefit effects on chronic sympathetic stimulus-induced cardiac fibrosis remains unclear. In this study, we determined to explore the role of ALDH2 on isoproterenol (ISO)-induced cardiac fibroblasts (CF) proliferation and cardiac fibrosis. It was found that ALDH2 enzymatic activity was impaired in ISO-induced HCF proliferation and Aldh2 deficiency promoted mouse CF proliferation. Alda-1, an ALDH2 activator, exerted obvious suppressive effect on ISO-induced HCF proliferation, together with the induction of cell cycle arrest at G₀/G₁ phase and decreased expression of cyclin E1 and cyclin-dependent kinase 2 (CDK2). Mechanistically, the inhibitory role of Alda-1 on HCF proliferation was achieved by decreasing mitochondrial reactive oxygen species (ROS) production, which was partially reversed by rotenone, an inducer of ROS. In addition, wild-type mice treated with Alda-1 manifested with reduced fibrosis and better cardiac function after ISO pump. In summary, Alda-1 alleviates sympathetic excitation-induced cardiac fibrosis via decreasing mitochondrial ROS accumulation, highlighting ALDH2 activity as a promising drug target of cardiac fibrosis.

在许多心血管疾病的发病机理中，交感神经心脏纤维化对疾病的进展和生存都具有重要意义。但是，临床上很少有针对它的有效疗法。醛脱氢酶2（ALDH2）的心脏保护作用已在许多病理条件下进行了研究，目前尚不清楚它能否对慢性交感刺激引起的心脏纤维化产生有益作用。在这项研究中，我们确定探索ALDH2在异丙肾上腺素（ISO）诱导的心脏成纤维细胞（CF）增殖和心脏纤维化中的作用。发现在ISO诱导的HCF增殖和Aldh2中，ALDH2的酶活性受到损害。缺乏会促进小鼠CF的增殖。Alda-1，一种ALDH2激活剂，对ISO诱导的HCF增殖具有明显的抑制作用，并诱导了G ₀ / G ₁处的细胞周期停滞周期蛋白E1和周期蛋白依赖性激酶2（CDK2）的表达降低。从机理上讲，Alda-1对HCF增殖的抑制作用是通过降低线粒体活性氧（ROS）的产生来实现的，该活性被ROS的诱导剂鱼藤酮部分逆转了。另外，用Alda-1处理的野生型小鼠在ISO泵后表现出纤维化减少和心脏功能更好的表现。总之，Alda-1通过减少线粒体ROS的积累减轻了交感神经诱发的心脏纤维化，突出了ALDH2活性作为有希望的心脏纤维化药物靶点。