Table_1_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.
History
References
- https://doi.org//10.1038/nature08030
- https://doi.org//10.1016/j.cmet.2016.05.006
- https://doi.org//10.1016/j.cmet.2012.04.022
- https://doi.org//10.1016/j.cmet.2015.05.023
- https://doi.org//10.1182/blood-2012-03-416776
- https://doi.org//10.1016/j.tips.2018.02.001
- https://doi.org//10.1038/cddis.2017.318
- https://doi.org//10.4161/auto.22971
- https://doi.org//10.1038/s41467-017-02352-z
- https://doi.org//10.1080/15548627.2015.1063768
- https://doi.org//10.15252/emmm.201404190
- https://doi.org//10.4161/auto.5655
- https://doi.org//10.1161/CIRCRESAHA.108.187427
- https://doi.org//10.1161/CIRCRESAHA.110.227371
- https://doi.org//10.1093/eurheartj/ehw224
- https://doi.org//10.3390/cells4030520
- https://doi.org//10.1161/CIRCRESAHA.109.203703
- https://doi.org//10.1016/s0305-4179(03)00204-3
- https://doi.org//10.1172/JCI82423
- https://doi.org//10.1016/j.tcb.2014.04.002
- https://doi.org//10.4161/auto.5603
- https://doi.org//10.1074/jbc.M112.363747
- https://doi.org//10.1038/nature05526
- https://doi.org//10.2337/db14-0325
- https://doi.org//10.1038/431031a
- https://doi.org//10.4161/auto.25969
- https://doi.org//10.1161/01.res.39.3.378
- https://doi.org//10.1016/j.molcel.2014.11.006
- https://doi.org//10.1038/35022604
- https://doi.org//10.1016/j.febslet.2015.05.042
- https://doi.org//10.3390/cells7120239
- https://doi.org//10.1111/mmi.12012
- https://doi.org//10.1038/nmeth.3630
- https://doi.org//10.1161/CIRCRESAHA.117.312317
- https://doi.org//10.1111/jcmm.12312
- https://doi.org//10.1016/j.molcel.2016.08.021
- https://doi.org//10.1016/j.bbadis.2019.05.007
- https://doi.org//10.1016/j.celrep.2017.12.061
- https://doi.org//10.1016/j.jprot.2012.09.024
- https://doi.org//10.1016/j.metabol.2015.11.010
- https://doi.org//10.1016/j.pharmthera.2018.06.004
- https://doi.org//10.1038/cr.2010.46
CC BY 4.0