BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.
BRD4 inhibition by JQ1 prevents high-fat diet-induced diabetic cardiomyopathy by activating PINK1/Parkin-mediated mitophagy in vivo.
复制标题
JQ 1抑制BRD 4通过激活体内PINK 1/Parkin介导的线粒体自噬来预防高脂饮食诱导的糖尿病心肌病
DOI：
10.1016/j.yjmcc.2020.09.003
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发表时间：
2020-12
影响因子：
5
通讯作者：
Zou MH
中科院分区：
文献类型：
--
作者：
Mu J;Zhang D;Tian Y;Xie Z;Zou MH
BRD 4是表观遗传调节因子的BET家族的成员。通过选择性布罗莫结构域抑制剂JQ 1抑制BRD 4，减轻胸主动脉缩窄诱导的心脏肥大和心力衰竭。然而，JQ 1对BRD 4的抑制是否对糖尿病性心肌病（2型糖尿病患者心力衰竭的主要原因）具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BRD 4和PINK 1/Parkin介导的线粒体自噬之间的新联系。糖尿病小鼠心脏中BRD 4的上调抑制PINK 1/Parkin介导的线粒体自噬，导致受损线粒体的积累和随后心脏结构和功能的损害。JQ 1抑制BRD 4可改善线粒体功能，修复糖尿病心脏的心脏结构和功能。这些效应依赖于BRD 4驱动的转录和PINK 1抑制的重新布线。Pink 1的缺失抑制线粒体自噬，加重心肌病，并消除JQ 1对糖尿病心肌病的治疗作用。我们的研究结果说明了通过抑制BRD 4治疗糖尿病心肌病的有效治疗策略。
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.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
影响因子：
16
作者：
Sakamaki JI;Wilkinson S;Hahn M;Tasdemir N;O'Prey J;Clark W;Hedley A;Nixon C;Long JS;New M;Van Acker T;Tooze SA;Lowe SW;Dikic I;Ryan KM
通讯作者：
Ryan KM
影响因子：
7.7
作者：
He C;Zhu H;Li H;Zou MH;Xie Z
通讯作者：
Xie Z
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1155/2012/329635
发表时间：
2012
期刊：
Journal of signal transduction
影响因子：
--
作者：
Marchi S;Giorgi C;Suski JM;Agnoletto C;Bononi A;Bonora M;De Marchi E;Missiroli S;Patergnani S;Poletti F;Rimessi A;Duszynski J;Wieckowski MR;Pinton P
通讯作者：
Pinton P