Department of Geriatrics, Linyi People's Hospital, Linyi, Shandong, China.
Department of Geriatrics, Linyi Jiaotong Hospital, Linyi, Shandong, China.
Toxicol Appl Pharmacol. 2018 Aug 1;352:9-18. doi: 10.1016/j.taap.2018.05.018. Epub 2018 May 18.
Diabetic cardiomyopathy is a cascade of complex events leading to eventual heart failure in diabetes. JQ1, one of Bromodomain and extra-terminal domain (BET) protein inhibitors, has exerted therapeutic effects on cancer proliferation, inflammation and cardiovascular disease. Recently, JQ1 was reported to protect mice from bleomycin-induced lung fibrosis and reverse the fibrotic response in carbon tetrachloride-induced liver fibrosis. However, its role in diabetic cardiomyopathy remains to be clarified. Our results indicated that JQ1 treatment suppressed cardiac fibrosis and improved cardiac function in a STZ-induced diabetic mouse model. We further used both cardiofibroblasts and cardiomyocytes in vitro to investigate the protective mechanism of JQ1. JQ1 significantly suppressed hyperglycemia-induced cardiofibroblasts proliferation and migration, myofibroblast differentiation, and collagen production. Moreover, JQ1 reduced hyperglycemia-induced apoptosis of cardiomyocytes in vitro and in vivo. Mechanistically, JQ1 treatment could reverse the expression of Caveolin-1, which modulates transforming growth factor-β1 (TGF-β1) signaling in cardiofibroblasts and inhibits cardiomyocytes apoptosis. Our findings identify BET inhibitor JQ1 as promising agent for diabetic cardiomyopathy.
糖尿病性心肌病是一系列复杂事件导致糖尿病患者最终心力衰竭。Bromodomain 和 extra-terminal 结构域（BET）蛋白抑制剂 JQ1 在癌症增殖、炎症和心血管疾病方面发挥了治疗作用。最近，JQ1 被报道可保护小鼠免受博来霉素诱导的肺纤维化，并逆转四氯化碳诱导的肝纤维化中的纤维化反应。然而，其在糖尿病性心肌病中的作用仍需阐明。我们的结果表明，JQ1 治疗可抑制 STZ 诱导的糖尿病小鼠模型中的心脏纤维化并改善心脏功能。我们进一步在体外使用心脏成纤维细胞和心肌细胞来研究 JQ1 的保护机制。JQ1 可显著抑制高血糖诱导的心脏成纤维细胞增殖和迁移、肌成纤维细胞分化和胶原产生。此外，JQ1 减少了体外和体内高血糖诱导的心肌细胞凋亡。机制上，JQ1 处理可逆转 Caveolin-1 的表达，该蛋白调节心脏成纤维细胞中的转化生长因子-β1（TGF-β1）信号传导，并抑制心肌细胞凋亡。我们的研究结果表明 BET 抑制剂 JQ1 是治疗糖尿病性心肌病的有前途的药物。
