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

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

doi:10.3389/fcell.2020.00191

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

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

Authors

Xingyue Zhang^{1

2}, Lingfei Li^{1

2}, Qiong Zhang^{1

2}, Qinglin Wei³, Jiezhi Lin^{1

2}, Jiezhi Jia^{1

2}, Junhui Zhang^{1

2}, Tiantian Yan⁴, Yanling Lv^{1

2}, Xupin Jiang^{1

2}, Peng Zhang^{1

2}, Huapei Song^{1

2}, Dongxia Zhang^{1

2}, Yuesheng Huang^{1

2

5}

Affiliations

¹ Institute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, China.
² State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, China.
³ Cholestatic Liver Diseases Center of the Institute of Digestive Disease, First Affiliated of Army Medical University, Chongqing, China.
⁴ Military Burn Center, The 990th (159th) Hospital of the People's Liberation Army, Zhumadian, China.
⁵ Department of Wound Repair, Institute of Wound Repair, The First Affiliated Hospital of South University of Science and Technology (Shenzhen Peoples Hospital), Shenzhen, China.

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.

Keywords: Rab7; autophagosome–lysosome fusion; heart disease; nicotinamide adenine dinucleotide; pleckstrin homology domain-containing protein family member 1.