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CD38在缺氧/缺血条件下通过转录抑制途径导致自噬通量抑制和心脏功能障碍。

CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions.

作者信息

Zhang Xingyue, Li Lingfei, Zhang Qiong, Wei Qinglin, Lin Jiezhi, Jia Jiezhi, Zhang Junhui, Yan Tiantian, Lv Yanling, Jiang Xupin, Zhang Peng, Song Huapei, Zhang Dongxia, Huang Yuesheng

机构信息

Institute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, China.

State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, China.

出版信息

Front Cell Dev Biol. 2020 Apr 17;8:191. doi: 10.3389/fcell.2020.00191. eCollection 2020.

DOI:10.3389/fcell.2020.00191
PMID:32363189
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7180518/
Abstract

Induced autophagy is protective against myocardial hypoxia/ischemia (H/I) injury, but evidence regarding the extent of autophagic clearance under H/I and the molecular mechanisms that influence autophagic flux has scarcely been presented. Here, we report that CD38 knockout improved cardiac function and autophagic flux in mice and neonatal cardiomyocytes (CMs) under H/I conditions. Mechanistic studies demonstrated that overexpression of CD38 specifically downregulated the expression of Rab7 and its adaptor protein pleckstrin homology domain-containing protein family member 1 (PLEKHM1) through nicotinamide adenine dinucleotide (NAD)-dependent and non-NAD-dependent pathways, respectively. Loss of Rab7/PLEKHM1 impaired the fusion of autophagosomes and lysosomes, resulting in autophagosome accumulation in the myocardium and consequent cardiac dysfunction under H/I conditions. Thus, CD38 mediated autophagic flux blockade and cardiac dysfunction in a Rab7/PLEKHM1-dependent manner. These findings suggest a potential therapeutic strategy involving targeted suppression of CD38 expression.

摘要

诱导自噬对心肌缺氧/缺血（H/I）损伤具有保护作用，但关于H/I条件下自噬清除程度以及影响自噬通量的分子机制的证据却鲜有报道。在此，我们报告CD38基因敲除可改善H/I条件下小鼠和新生心肌细胞（CMs）的心脏功能和自噬通量。机制研究表明，CD38的过表达分别通过烟酰胺腺嘌呤二核苷酸（NAD）依赖和非NAD依赖途径特异性下调Rab7及其衔接蛋白含pleckstrin同源结构域蛋白家族成员1（PLEKHM1）的表达。Rab7/PLEKHM1的缺失损害了自噬体与溶酶体的融合，导致心肌中自噬体积累，并在H/I条件下引发心脏功能障碍。因此，CD38以Rab7/PLEKHM1依赖的方式介导自噬通量阻断和心脏功能障碍。这些发现提示了一种涉及靶向抑制CD38表达的潜在治疗策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f55/7180518/6ad260de6bcb/fcell-08-00191-g008.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f55/7180518/9ebfbea6f567/fcell-08-00191-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0f55/7180518/6ad260de6bcb/fcell-08-00191-g008.jpg
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