BRD4 is a member of the BET family of epigenetic regulators. Inhibition of BRD4 by the selective bromodomain inhibitor JQ1, alleviates thoracic aortic constriction-induced cardiac hypertrophy and heart failure. However, whether BRD4 inhibition by JQ1 has therapeutic effect on diabetic cardiomyopathy, a major cause of heart failure in patients with Type 2 diabetes, remains unknown. Here, we discover a novel link between BRD4 and PINK1/Parkin-mediated mitophagy during diabetic cardiomyopathy. Upregulation of BRD4 in diabetic mouse hearts inhibits PINK1/Parkin-mediated mitophagy, resulting in accumulation of damaged mitochondria and subsequent impairment of cardiac structure and function. BRD4 inhibition by JQ1 improves mitochondrial function, and repairs the cardiac structure and function of the diabetic heart. These effects depended on rewiring of the BRD4-driven transcription and repression of PINK1. Deletion of Pink1 suppresses mitophagy, exacerbates cardiomyopathy, and abrogates the therapeutic effect of JQ1 on diabetic cardiomyopathy. Our results illustrate a valid therapeutic strategy for treating diabetic cardiomyopathy by inhibition of BRD4.

BRD4 是 BET 表观遗传调节因子家族的成员。选择性溴结构域抑制剂 JQ1 抑制 BRD4，减轻胸主动脉收缩引起的心脏肥大和心力衰竭。然而，JQ1 对 BRD4 的抑制是否对糖尿病心肌病（2 型糖尿病患者心力衰竭的主要原因）有治疗作用仍然未知。在这里，我们发现了糖尿病心肌病期间 BRD4 和 PINK1/Parkin 介导的线粒体自噬之间的新联系。糖尿病小鼠心脏中 BRD4 的上调抑制了 PINK1/Parkin 介导的线粒体自噬，导致受损线粒体的积累和随后的心脏结构和功能受损。JQ1对BRD4的抑制改善了线粒体功能，并修复了糖尿病心脏的心脏结构和功能。这些影响取决于 BRD4 驱动转录的重新布线和 PINK1 的抑制。删除Pink1抑制线粒体自噬，加剧心肌病，并消除 JQ1 对糖尿病心肌病的治疗作用。我们的结果说明了通过抑制 BRD4 治疗糖尿病心肌病的有效治疗策略。