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

作者：Xingyue Zhang, Lingfei Li, Qiong Zhang, Qinglin Wei, Jiezhi Lin, Jiezhi Jia, Junhui Zhang, Tiantian Yan, Yanling Lv, Xupin Jiang, Peng Zhang, Huapei Song, Dongxia Zhang, Yuesheng Huang · 发表于：Frontiers in Cell and Developmental Biology · 年份：2020 · DOI：10.3389/fcell.2020.00191 · 被引用次数：31 · 研究领域：Calcium signaling and nucleotide metabolism、Autophagy in Disease and Therapy、Sirtuins and Resveratrol in Medicine

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 CD38-/- mice and CD38-/- 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.