Table_2_CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions.doc

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.

细胞自噬（autophagy）对心肌缺氧/缺血（H/I）损伤具有保护作用，但目前关于H/I状态下自噬清除程度以及调控自噬流（autophagic flux）的分子机制的相关研究证据仍鲜有报道。本研究发现，在H/I条件下，CD38敲除可改善CD38基因敲除（CD38–/–）小鼠以及CD38–/–新生心肌细胞（cardiomyocytes, CMs）的心功能与自噬流水平。机制研究表明，CD38过表达可分别通过烟酰胺腺嘌呤二核苷酸（nicotinamide adenine dinucleotide, NAD）依赖与非NAD依赖途径，特异性下调Rab7及其接头蛋白含pleckstrin同源结构域家族成员1（PLEKHM1）的表达。Rab7/PLEKHM1的缺失会损伤自噬体与溶酶体的融合过程，导致心肌组织中自噬体堆积，并在H/I条件下引发心功能障碍。综上，CD38可通过依赖Rab7/PLEKHM1的方式介导自噬流阻断与心功能损伤。上述研究结果提示，靶向抑制CD38表达或可成为治疗心肌H/I损伤的潜在策略。