Lee Hsiao-Lin, Hee Siow-Wey, Hsuan Chin-Feng, Yang Wenjin, Huang Jing-Yong, Lin Ya-Ling, Hsu Chih-Neng, Hwang Juey-Jen, Chen Shiau-Mei, Ding Zhi-Zhong, Lee Tung-Yuan, Lin Yu-Chiao, Tsai Feng-Chiao, Su Wei-Lun, Chueh Li-Yun, Hsieh Meng-Lun, Chen Che-Hong, Mochly-Rosen Daria, Chang Yi-Cheng, Chuang Lee-Ming
Department of Internal Medicine, National Taiwan University Hospital, Taipei 100225, Taiwan.
Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung 824410, Taiwan.
Antioxidants (Basel). 2021 Mar 13;10(3):450. doi: 10.3390/antiox10030450.
Diabetes mellitus has reached epidemic proportion worldwide. One of the diabetic complications is cardiomyopathy, characterized by early left ventricular (LV) diastolic dysfunction, followed by development of systolic dysfunction and ventricular dilation at a late stage. The pathogenesis is multifactorial, and there is no effective treatment yet. In recent years, 4-hydroxy-2-nonenal (4-HNE), a toxic aldehyde generated from lipid peroxidation, is implicated in the pathogenesis of cardiovascular diseases. Its high bioreactivity toward proteins results in cellular damage. Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that detoxifies 4-HNE. The development of small-molecule ALDH2 activator provides an opportunity for treating diabetic cardiomyopathy. This study found that AD-9308, a water-soluble andhighly selective ALDH2 activator, can improve LV diastolic and systolic functions, and wall remodeling in streptozotocin-induced diabetic mice. AD-9308 treatment dose-dependently lowered serum 4-HNE levels and 4-HNE protein adducts in cardiac tissue from diabetic mice, accompanied with ameliorated myocardial fibrosis, inflammation, and apoptosis. Improvements of mitochondrial functions, sarco/endoplasmic reticulumcalcium handling and autophagy regulation were also observed in diabetic mice with AD-9308 treatment. In conclusion, ADLH2 activation effectively ameliorated diabetic cardiomyopathy, which may be mediated through detoxification of 4-HNE. Our findings highlighted the therapeutic potential of ALDH2 activation for treating diabetic cardiomyopathy.
糖尿病在全球已呈流行态势。糖尿病并发症之一是心肌病，其特征为早期左心室舒张功能障碍，随后在晚期出现收缩功能障碍和心室扩张。发病机制是多因素的，目前尚无有效治疗方法。近年来，4-羟基-2-壬烯醛（4-HNE）这种由脂质过氧化产生的有毒醛类，被认为与心血管疾病的发病机制有关。它对蛋白质具有高生物反应性，会导致细胞损伤。线粒体醛脱氢酶2（ALDH2）是使4-HNE解毒的主要酶。小分子ALDH2激活剂的研发为治疗糖尿病心肌病提供了契机。本研究发现，AD-9308这种水溶性且高度选择性的ALDH2激活剂，可改善链脲佐菌素诱导的糖尿病小鼠的左心室舒张和收缩功能以及心肌重塑。AD-9308治疗可剂量依赖性降低糖尿病小鼠心脏组织中的血清4-HNE水平和4-HNE蛋白加合物，同时改善心肌纤维化、炎症和细胞凋亡。在接受AD-9308治疗的糖尿病小鼠中还观察到线粒体功能、肌浆网/内质网钙处理和自噬调节的改善。总之，激活ALDH2可有效改善糖尿病心肌病，这可能是通过4-HNE解毒介导的。我们的研究结果突出了激活ALDH2在治疗糖尿病心肌病方面的治疗潜力。
