CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions
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...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Cell and Developmental Biology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fcell.2020.00191/full |
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| record_format |
Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions Frontiers in Cell and Developmental Biology pleckstrin homology domain-containing protein family member 1 Rab7 nicotinamide adenine dinucleotide autophagosome–lysosome fusion heart disease |
| author_facet |
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 |
| author_sort |
Xingyue Zhang |
| title |
CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions |
| title_short |
CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions |
| title_full |
CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions |
| title_fullStr |
CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions |
| title_full_unstemmed |
CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia Conditions |
| title_sort |
cd38 causes autophagic flux inhibition and cardiac dysfunction through a transcriptional inhibition pathway under hypoxia/ischemia conditions |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Cell and Developmental Biology |
| issn |
2296-634X |
| publishDate |
2020-04-01 |
| description |
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. |
| topic |
pleckstrin homology domain-containing protein family member 1 Rab7 nicotinamide adenine dinucleotide autophagosome–lysosome fusion heart disease |
| url |
https://www.frontiersin.org/article/10.3389/fcell.2020.00191/full |
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1724583615447171072 |
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doaj-527cb56792a14185abd7181c5d4e674b2020-11-25T03:28:31ZengFrontiers Media S.A.Frontiers in Cell and Developmental Biology2296-634X2020-04-01810.3389/fcell.2020.00191518830CD38 Causes Autophagic Flux Inhibition and Cardiac Dysfunction Through a Transcriptional Inhibition Pathway Under Hypoxia/Ischemia ConditionsXingyue Zhang0Xingyue Zhang1Lingfei Li2Lingfei Li3Qiong Zhang4Qiong Zhang5Qinglin Wei6Jiezhi Lin7Jiezhi Lin8Jiezhi Jia9Jiezhi Jia10Junhui Zhang11Junhui Zhang12Tiantian Yan13Yanling Lv14Yanling Lv15Xupin Jiang16Xupin Jiang17Peng Zhang18Peng Zhang19Huapei Song20Huapei Song21Dongxia Zhang22Dongxia Zhang23Yuesheng Huang24Yuesheng Huang25Yuesheng Huang26Institute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaCholestatic Liver Diseases Center of the Institute of Digestive Disease, First Affiliated of Army Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaMilitary Burn Center, The 990th (159th) Hospital of the People’s Liberation Army, Zhumadian, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaInstitute of Burn Research, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaState Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University, Third Military Medical University, Chongqing, ChinaDepartment of Wound Repair, Institute of Wound Repair, The First Affiliated Hospital of South University of Science and Technology (Shenzhen Peoples Hospital), Shenzhen, ChinaInduced 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.https://www.frontiersin.org/article/10.3389/fcell.2020.00191/fullpleckstrin homology domain-containing protein family member 1Rab7nicotinamide adenine dinucleotideautophagosome–lysosome fusionheart disease |