Guangdong Engineering & Technology Research Center for Disease-Model Animals, Laboratory Animal Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, Guangdong, China.
Nat Commun. 2023 Mar 2;14(1):1181. doi: 10.1038/s41467-023-36837-x.
Diabetic cardiomyopathy is a primary myocardial injury induced by diabetes with complex pathogenesis. In this study, we identify disordered cardiac retinol metabolism in type 2 diabetic male mice and patients characterized by retinol overload, all-trans retinoic acid deficiency. By supplementing type 2 diabetic male mice with retinol or all-trans retinoic acid, we demonstrate that both cardiac retinol overload and all-trans retinoic acid deficiency promote diabetic cardiomyopathy. Mechanistically, by constructing cardiomyocyte-specific conditional retinol dehydrogenase 10-knockout male mice and overexpressing retinol dehydrogenase 10 in male type 2 diabetic mice via adeno-associated virus, we verify that the reduction in cardiac retinol dehydrogenase 10 is the initiating factor for cardiac retinol metabolism disorder and results in diabetic cardiomyopathy through lipotoxicity and ferroptosis. Therefore, we suggest that the reduction of cardiac retinol dehydrogenase 10 and its mediated disorder of cardiac retinol metabolism is a new mechanism underlying diabetic cardiomyopathy.
糖尿病性心肌病是由糖尿病引起的原发性心肌损伤，其发病机制复杂。在本研究中，我们发现 2 型糖尿病雄性小鼠和患者存在视黄醇代谢紊乱，表现为视黄醇过载和全反式视黄酸缺乏。通过给 2 型糖尿病雄性小鼠补充视黄醇或全反式视黄酸，我们证明心脏视黄醇过载和全反式视黄酸缺乏均促进糖尿病性心肌病。从机制上讲，通过构建心肌细胞特异性条件性视黄醇脱氢酶 10 敲除雄性小鼠，并通过腺相关病毒在雄性 2 型糖尿病小鼠中过表达视黄醇脱氢酶 10，我们验证了心脏视黄醇脱氢酶 10 的减少是心脏视黄醇代谢紊乱的起始因素，并通过脂毒性和铁死亡导致糖尿病性心肌病。因此，我们认为心脏视黄醇脱氢酶 10 的减少及其介导的心脏视黄醇代谢紊乱是糖尿病性心肌病的一个新机制。
