靶向糖吞噬ATG8治疗在小鼠和人类工程心脏组织中逆转糖尿病性心脏病。

IF 10.8 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
K M Mellor, U Varma, P Koutsifeli, C L Curl, J V Janssens, L J Daniels, G B Bernasochi, A J A Raaijmakers, M Annandale, X Li, S L James, D J Taylor, K Raedschelders, K L Weeks, R J Mills, R G Parton, X Hu, J R Bell, T J O'Brien, R Katare, E R Porrello, J E Hudson, R P Xiao, J E Van Eyk, R A Gottlieb, L M D Delbridge
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引用次数: 0

摘要

糖尿病性心脏病非常普遍,并与舒张舒张受损的早期发展有关。糖尿病性心脏病的发病机制尚不清楚,而且目前还没有针对性的治疗方法。最近,在糖尿病心脏中发现了糖原自噬(glycophagy)和糖原积累的中断。糖吞噬涉及糖原受体与ATG8蛋白结合,在细胞内吞噬溶酶体中定位和降解糖原。本研究表明糖原受体蛋白淀粉结合域蛋白1 (STBD1)在体内对代谢挑战的心脏糖原反应的早期被动员,并且特异性ATG8家族蛋白γ-氨基丁酸a型受体相关蛋白样1 (GABARAPL1)的缺乏与糖尿病舒张功能障碍有关。Gabarapl1基因递送治疗可修复2型糖尿病小鼠的心肌细胞和心脏舒张功能障碍,以及“糖尿病”人类诱导的多能干细胞衍生的心脏类器官的舒张功能。我们确定糖吞噬失调是糖尿病性心脏病的机制和潜在的治疗靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Targeted glycophagy ATG8 therapy reverses diabetic heart disease in mice and in human engineered cardiac tissues.

Diabetic heart disease is highly prevalent and is associated with the early development of impaired diastolic relaxation. The mechanisms of diabetic heart disease are poorly understood, and it is a condition for which there are no targeted therapies. Recently, disrupted glycogen autophagy (glycophagy) and glycogen accumulation have been identified in the diabetic heart. Glycophagy involves glycogen receptor binding and linking with an ATG8 protein to locate and degrade glycogen within an intracellular phagolysosome. Here we show that glycogen receptor protein starch binding domain protein 1 (STBD1) is mobilized early in the cardiac glycogen response to metabolic challenge in vivo, and that deficiency of a specific ATG8 family protein, γ-aminobutyric acid type A receptor-associated protein-like 1 (GABARAPL1), is associated with diastolic dysfunction in diabetes. Gabarapl1 gene delivery treatment remediated cardiomyocyte and cardiac diastolic dysfunction in type 2 diabetic mice and the diastolic performance of 'diabetic' human induced pluripotent stem cell-derived cardiac organoids. We identify glycophagy dysregulation as a mechanism and potential treatment target for diabetic heart disease.

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