title: CD38 Deficiency Protects the Heart from Ischemia/Reperfusion Injury through Activating SIRT1/FOXOs-Mediated Antioxidative Stress Pathway.
abstract: Ischemia/reperfusion (I/R) injury induces irreversible oxidative stress damage to the cardiac muscle. We previously observed that CD38 deficiency remarkably protects mouse embryonic fibroblasts (MEFs) from oxidative stress-induced injury. However, whether CD38 deficiency protects from I/R injury in the heart is not explored. Here, we showed that the hearts of CD38 deficient mice or wild type mice supplied with exogenous NAD were significantly protected from ischemia/reperfusion injury, seen as reduction of the myocardial infarct sizes when the mice were subjected to 30 min ischemia followed by 24 hours of reperfusion. Consistently, the protection of CD38 deficiency on hypoxia/reoxygenation (H/R) injury was confirmed with a CD38 knockdown H9c2 stable cell line. Furthermore, we observed that knockdown of CD38 remarkably inhibited ROS generation and intracellular Ca(2+) overloading induced by H/R in H9c2 cells. The FOXO1 and FOXO3 expressions were significantly elevated by H/R injury in CD38 knockdown cells compared with normal H9c2 cells. The cell immunofluorescence assay showed that FOXO1 nuclear translocation was significantly increased in CD38 knockdown H9c2 cells. In addition, we demonstrated that the increase of FOXO1 nuclear translocation was associated with the increased expressions of antioxidant catalase and SOD2 and the attenuated expression of the ROS generation enzyme NOX4. In conclusion, our results provide new evidence that CD38 deficiency protects the heart from I/R injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway.
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Guan
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Hong
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xiao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Ling-Fang
authors.initials: LF
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Ling
authors.identifier: 0000-0002-6710-9137
authors.initials: L
authors.lastname: Tang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Kai
authors.identifier: 0000-0001-7429-3924
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Yi-Song
authors.initials: YS
authors.lastname: Qian
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Ke-Yu
authors.initials: KY
authors.lastname: Deng
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Guangju
authors.initials: G
authors.lastname: Ji
authors.affiliation: Department of Basic Medical Science, Shock/Trauma Research Center, School of Medicine, University of Missouri-Kansas City, Kansas City, MO 64108, USA.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang 330031, China.
authors.forename: Hong-Bo
authors.identifier: 0000-0002-4257-207X
authors.initials: HB
authors.lastname: Xin
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000172:deficiency* / Q000235:genetics; D051997:ADP-ribosyl Cyclase 1 / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004195:Disease Models, Animal; D000071316:Forkhead Box Protein O3 / Q000378:metabolism*; D005838:Genotype; D008297:Male; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000201:enzymology / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D018384:Oxidative Stress; D010641:Phenotype; D034622:RNA Interference; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000378:metabolism*; D014162:Transfection; D000071161:Forkhead Box Protein O1
chemical_list: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium; D000071316:Forkhead Box Protein O3; D008562:Membrane Glycoproteins; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; D009419:Nerve Tissue Proteins; D017382:Reactive Oxygen Species; D056564:Sirtuin 1; C499515:FOXO3 protein, rat; C074639:Foxo1 protein, rat; D000071161:Forkhead Box Protein O1; C498911:Nox4 protein, rat; C498155:Cd38 protein, mouse; C498156:Cd38 protein, rat; C488368:Sirt1 protein, rat