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

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

doi:10.3389/fcell.2020.00191

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 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.

Highlights

Autophagy is an intracellular lysosomal degradative process that supports cellular homeostasis and survival through quality control of amino acid pools and energy metabolism (Gustafsson and Gottlieb, 2009; Zhang et al, 2018)
Our study indicated that overexpression of CD38 accelerated the progression of cardiac dysfunction and worsened outcomes under H/I conditions by blocking autophagic flux through nicotinamide adenine dinucleotide (NAD)-dependent and NADindependent pathways
We found that the mice were protected against cardiac dysfunction after burn injury and that this benefit was lost when the mice were treated with CQ, an inhibitor of autophagy that impairs the fusion of autophagosomes and lysosomes

Summary

Introduction

Autophagy is an intracellular lysosomal degradative process that supports cellular homeostasis and survival through quality control of amino acid pools and energy metabolism (Gustafsson and Gottlieb, 2009; Zhang et al, 2018). Autophagosome prevalence, commonly regarded as an index of the state of autophagic activation, is determined by the rates of autophagosome formation and clearance. Frequent observations of autophagosomes in dying cells have aroused interest in autophagy as a potential mechanism for a cell death process called type II programmed cell death. It is not clear whether the increased abundance of autophagosomes in dying cells reflects upregulation of effective autophagy or impairment of autophagic flux with reduced clearance of accumulated autophagosomes (Klionsky, 2004) followed by secondary activation of programmed cell death (Nishino et al, 2000; Yang et al, 2019)

Objectives

Results

Conclusion