在糖尿病患者的心脏中,USP28作为线粒体形态功能缺陷和心脏功能障碍的关键抑制剂
Sai-Yang Xie1,2, Shi-Qiang Liu1,2, Tong Zhang1,2
1Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, P.R. China (S.-y.X, S.-q.L., T.Z., W.-k.S., Y.X., W.-x.F., M.Z., M.-Y.C., L.-l.L., H.Z., N.Z., W.D., Q.z.T.).
Circulation
|November 23, 2023
概括
这项研究显示,通过稳定PPARα和促进Mfn2来保护Ubiquitin特异蛋白酶28 (USP28). 针对USP28的USP28激活或AAV治疗为糖尿病心脏病提供了有前途的治疗策略.
科学领域:
- 心脏病学
- 代谢疾病
- 分子生物学
背景情况:
- 糖尿病心肌病是一种常见的糖尿病并发症,导致心力衰竭.
- 传统疗法不足以阻止糖尿病心肌病的进展.
- 研究了USP28 (乌比基特异蛋白酶28) 在糖尿病心肌病的代谢脆弱性中的作用.
研究的目的:
- 评估USP28在糖尿病心肌病中的潜在作用和治疗价值.
- 阐明USP28在糖尿病心脏中的作用的分子机制.
主要方法:
- 使用了2型糖尿病小鼠模型 (db/db,HFD/STZ) 和心脏特异性的USP28淘汰小鼠.
- 使用新生小鼠心室肌细胞和人类iPSC衍生的心肌细胞的体外模型.
- 通过RNA测序,IP/MS,ChIP-seq和蛋白质拉下测试来研究分子机制.
主要成果:
- 在糖尿病心脏中观察到USP28表达的减少 (小鼠和患者).
- 缺乏USP28会加剧心脏功能障碍和脂质积累;过度表达USP28会改善心脏功能和减少纤维化.
- USP28与PPARα直接相互作用,使其稳定以促进Mfn2转录,从而防止线粒体功能障碍.
结论:
- 在糖尿病心脏中,USP28通过PPARα-Mfn2轴调节线粒体平衡.
- 在糖尿病心肌病中,USP28激活或AAV介导的USP28治疗是潜在的治疗策略.
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