title: Tumor suppressor A20 protects against cardiac hypertrophy and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling.
abstract: A20 or tumor necrosis factor-induced protein 3 is a negative regulator of nuclear factor kappaB signaling. A20 has been shown previously to attenuate cardiac hypertrophy in vitro and postmyocardial infarction remodeling in vivo. In the present study, we tested the hypothesis that overexpression of A20 in the murine heart would protect against cardiac hypertrophy in vivo. The effects of constitutive human A20 expression on cardiac hypertrophy were investigated using in vitro and in vivo models. Cardiac hypertrophy was produced by aortic banding in A20 transgenic mice and control animals. The extent of cardiac hypertrophy was quantitated by echocardiography, as well as by pathological and molecular analyses of heart samples. Constitutive overexpression of human A20 in the murine heart attenuated the hypertrophic response and markedly reduced inflammation, apoptosis, and fibrosis. Cardiac function was also preserved in hearts with increased A20 levels in response to hypertrophic stimuli. Western blot experiments further showed A20 expression markedly blocked transforming growth factor-beta-activated kinase 1-dependent c-Jun N-terminal kinase/p38 signaling cascade but with no difference in either extracellular signal-regulated kinase 1/2 or AKT activation in vivo and in vitro. In cultured neonatal rat cardiac myocytes, [3H]proline incorporation and Western blot assays revealed that A20 expression suppressed transforming growth factor-beta-induced collagen synthesis and transforming growth factor-beta-activated kinase 1-dependent Smad 2/3/4 activation. In conclusion, A20 improves cardiac functions and inhibits cardiac hypertrophy, inflammation, apoptosis, and fibrosis by blocking transforming growth factor-beta-activated kinase 1-dependent signaling.
authors.affiliation: Department of Cardiology of Renmin Hospital, Wuhan University, Wuhan 430060, People's Republic of China. lihl@whu.edu.cn
authors.forename: He
authors.initials: H
authors.lastname: Huang
authors.forename: Qi-Zhu
authors.initials: QZ
authors.lastname: Tang
authors.forename: Ai-Bing
authors.initials: AB
authors.lastname: Wang
authors.forename: Manyin
authors.initials: M
authors.lastname: Chen
authors.forename: Ling
authors.initials: L
authors.lastname: Yan
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Jiang
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Yang
authors.forename: Zhou-Yan
authors.initials: ZY
authors.lastname: Bian
authors.forename: Xue
authors.initials: X
authors.lastname: Bai
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhu
authors.forename: Lang
authors.initials: L
authors.lastname: Wang
authors.forename: Hongliang
authors.initials: H
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D001835:Body Weight; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D004719:Endomyocardial Fibrosis / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006321:Heart / Q000033:anatomy & histology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000502:physiology*; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D032342:Muscle Cells / Q000166:cytology / Q000502:physiology; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009929:Organ Size; D051381:Rats; D013314:Stress, Mechanical; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors*; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D009687:Nuclear Proteins; D053773:Transforming Growth Factor beta1; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D000099151:MAP Kinase Kinase Kinase 7; C076529:TNFAIP3 protein, human