Frontiers in Cell and Developmental Biology (Apr 2020)

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

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

DOI
https://doi.org/10.3389/fcell.2020.00191
Journal volume & issue
Vol. 8

Abstract

Read online

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.

Keywords