title: CD38 promotes angiotensin II-induced cardiac hypertrophy.
abstract: Cardiac hypertrophy is an early hallmark during the clinical course of heart failure and regulated by various signalling pathways. Recently, we observed that mouse embryonic fibroblasts from CD38 knockout mice were significantly resistant to oxidative stress such as H2O2-induced injury and hypoxia/reoxygenation-induced injury. In addition, we also found that CD38 knockout mice protected heart from ischaemia reperfusion injury through activating SIRT1/FOXOs-mediated antioxidative stress pathway. However, the role of CD38 in cardiac hypertrophy is not explored. Here, we investigated the roles and mechanisms of CD38 in angiotensin II (Ang-II)-induced cardiac hypertrophy. Following 14 days of Ang-II infusion with osmotic mini-pumps, a comparable hypertension was generated in both of CD38 knockout and wild-type mice. However, the cardiac hypertrophy and fibrosis were much more severe in wild-type mice compared with CD38 knockout mice. Consistently, RNAi-induced knockdown of CD38 decreased the gene expressions of atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) and reactive oxygen species generation in Ang-II-stimulated H9c2 cells. In addition, the expression of SIRT3 was elevated in CD38 knockdown H9c2 cells, in which SIRT3 may further activate the FOXO3 antioxidant pathway. The intracellular Ca2+release induced by Ang-II markedly decreased in CD38 knockdown H9c2 cells, which might be associated with the decrease of nuclear translocation of NFATc4 and inhibition of ERK/AKT phosphorylation. We concluded that CD38 plays an essential role in cardiac hypertrophy probably via inhibition of SIRT3 expression and activation of Ca2+-NFAT signalling pathway. Thus, CD38 may be a novel target for treating cardiac hypertrophy.
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Xiao-Hui
authors.initials: XH
authors.lastname: Guan
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Xuan
authors.initials: X
authors.lastname: Hong
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zhao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Xiao-Hong
authors.initials: XH
authors.lastname: Liu
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xiao
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Ting-Tao
authors.initials: TT
authors.lastname: Chen
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Li-Bin
authors.initials: LB
authors.lastname: Deng
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Xiao-Lei
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Jian-Bin
authors.initials: JB
authors.lastname: Wang
authors.affiliation: National Laboratory of Biomacromolecules, Institute of Biophysics Chinese Academy of Sciences, Beijing, China.
authors.forename: Guang-Ju
authors.initials: GJ
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, USA.
authors.forename: Mingui
authors.initials: M
authors.lastname: Fu
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Ke-Yu
authors.initials: KY
authors.lastname: Deng
authors.affiliation: Institute of Translational Medicine, Nanchang University, Nanchang, China.
authors.forename: Hong-Bo
authors.identifier: 0000-0002-4257-207X
authors.initials: HB
authors.lastname: Xin
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism; D005786:Gene Expression Regulation; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000235:genetics / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism
chemical_list: C499515:FOXO3 protein, rat; D000071316:Forkhead Box Protein O3; D008562:Membrane Glycoproteins; D050778:NFATC Transcription Factors; D009419:Nerve Tissue Proteins; C477593:Nfatc4 protein, rat; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; C000607791:SIRT3 protein, rat; D000804:Angiotensin II; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C498155:Cd38 protein, mouse; D051997:ADP-ribosyl Cyclase 1; D037761:Sirtuins; D002118:Calcium
keywords: CD38; NFATc4; SIRT3; angiotensin II; cardiac hypertrophy