title: Cytosolic CARP promotes angiotensin II- or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation.
abstract: The gene ankyrin repeat domain 1 (Ankrd1) is an enigmatic gene and may exert pleiotropic function dependent on its expression level, subcellular localization and even types of pathological stress, but it remains unclear how these factors influence the fate of cardiomyocytes. Here we attempted to investigate the role of CARP on cardiomyocyte hypertrophy. In neonatal rat ventricular cardiomyocytes (NRVCs), angiotensin II (Ang II) increased the expression of both calpain 1 and CARP, and also induced cytosolic translocation of CARP, which was abrogated by a calpain inhibitor. In the presence of Ang-II in NRVCs, infection with a recombinant adenovirus containing rat Ankrd1 cDNA (Ad-Ankrd1) enhanced myocyte hypertrophy, the upregulation of atrial natriuretic peptide and β-myosin heavy chain genes and calcineurin proteins as well as nuclear translocation of nuclear factor of activated T cells. Cyclosporin A attenuated Ad-Ankrd1-enhanced cardiomyocyte hypertrophy. Intra-myocardial injection of Ad-Ankrd1 in mice with transverse aortic constriction (TAC) markedly increased the cytosolic CARP level, the heart weight/body weight ratio, while short hairpin RNA targeting Ankrd1 inhibited TAC-induced hypertrophy. The expression of calcineurin was also significantly increased in Ad-Ankrd1-infected TAC mice. Olmesartan (an Ang II receptor antagonist) prevented the upregulation of CARP in both Ang II-stimulated NRVCs and hearts with pressure overload. These findings indicate that overexpression of Ankrd1 exacerbates pathological cardiac remodeling through the enhancement of cytosolic translocation of CARP and upregulation of calcineurin.
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Ci
authors.initials: C
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Shen
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Shiping
authors.initials: S
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xixian
authors.initials: X
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Wanling
authors.initials: W
authors.lastname: Xuan
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jingwen
authors.initials: J
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Huang
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Bin
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Dingli
authors.initials: D
authors.lastname: Xu
authors.affiliation: Department of Pharmacy, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Guofeng
authors.initials: G
authors.lastname: Li
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China; Cardiovascular Division of the Department of Medicine, National Cerebral and Cardiovascular Center, Osaka, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Kitakaze
authors.affiliation: State Key Laboratory of Organ Failure Research, Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Liao
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001011:Aorta / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000235:genetics / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003251:Constriction, Pathologic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016572:Cyclosporine / Q000494:pharmacology; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D006023:Glycoproteins / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D009124:Muscle Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D061251:Primary Cell Culture; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology
chemical_list: C491303:Ankrd1 protein, rat; D006023:Glycoproteins; D007093:Imidazoles; C000594638:MYH7 protein, rat; D009124:Muscle Proteins; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D013777:Tetrazoles; C039304:calpain inhibitors; D000804:Angiotensin II; D016572:Cyclosporine; D009320:Atrial Natriuretic Factor; C437965:olmesartan; D019703:Calcineurin; D002154:Calpain; D018995:Myosin Heavy Chains
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