title: Tripartite motif 32 prevents pathological cardiac hypertrophy.
abstract: TRIM32 (tripartite motif 32) is widely accepted to be an E3 ligase that interacts with and eventually ubiquitylates multiple substrates. TRIM32 mutants have been associated with LGMD-2H (limb girdle muscular dystrophy 2H). However, whether TRIM32 is involved in cardiac hypertrophy induced by biomechanical stresses and neurohumoral mediators remains unclear. We generated mice and isolated NRCMs (neonatal rat cardiomyocytes) that overexpressed or were deficient in TRIM32 to investigate the effect of TRIM32 on AB (aortic banding) or AngII (angiotensin II)-mediated cardiac hypertrophy. Echocardiography and both pathological and molecular analyses were used to determine the extent of cardiac hypertrophy and subsequent fibrosis. Our results showed that overexpression of TRIM32 in the heart significantly alleviated the hypertrophic response induced by pressure overload, whereas TRIM32 deficiency dramatically aggravated pathological cardiac remodelling. Similar results were also found in cultured NRCMs incubated with AngII. Mechanistically, the present study suggests that TRIM32 exerts cardioprotective action by interruption of Akt- but not MAPK (mitogen-dependent protein kinase)-dependent signalling pathways. Additionally, inactivation of Akt by LY294002 offset the exacerbated hypertrophic response induced by AB in TRIM32-deficient mice. In conclusion, the present study indicates that TRIM32 plays a protective role in AB-induced pathological cardiac remodelling by blocking Akt-dependent signalling. Therefore TRIM32 could be a novel therapeutic target for the prevention of cardiac hypertrophy and heart failure.
authors.affiliation: Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Jiangsu 210009, P.R. China lihl@whu.edu.cn chenlijuan@seu.edu.cn.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Jiangsu 210009, P.R. China.
authors.forename: Jia
authors.initials: J
authors.lastname: Huang
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Yanxiao
authors.initials: Y
authors.lastname: Ji
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Xiaojing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Pixiao
authors.initials: P
authors.lastname: Wang
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Keqiong
authors.initials: K
authors.lastname: Deng
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China.
authors.forename: Xi
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Department of Cardiology, Zhongda Hospital Affiliated to Southeast University, Jiangsu 210009, P.R. China.
authors.forename: Genshan
authors.initials: G
authors.lastname: Ma
authors.affiliation: Animal Experiment Center/Animal Biosafety Level-III Laboratory, Wuhan University, Wuhan, 430072, P.R. China lihl@whu.edu.cn chenlijuan@seu.edu.cn.
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D004452:Echocardiography / Q000379:methods; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D006801:Humans; D008297:Male; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D014157:Transcription Factors; D000070584:Tripartite Motif Proteins; D000804:Angiotensin II; C094027:TRIM32 protein, human; C514011:TRIM32 protein, mouse; D044767:Ubiquitin-Protein Ligases; C000617052:trim32 protein, rat
keywords: Akt; TRIM32; cardiac dysfunction; cardiac hypertrophy; signalling pathway