title: Tumor suppressor gene ING3 induces cardiomyocyte hypertrophy via inhibition of AMPK and activation of p38 MAPK signaling.
abstract: Cardiac hypertrophy, an adaptive growth process that occurs in response to various pathophysiological stimuli, constitutes an important risk factor for the development of heart failure. However, the molecular mechanisms that regulate this cardiac growth response are not completely understood. Here we revealed that ING3 (inhibitor of growth family, member 3), a type II tumor suppressor, plays a critical role in the regulation of cardiac hypertrophy. ING3 expression was present in relatively high abundance in the heart, and was prominently upregulated in hypertrophic agonists angiotensin II (Ang II), phenylephrine (PE), or isoproterenol (ISO)-stimulated cardiomyocytes and in hearts of rat undergoing abdominal aortic constriction (AAC) surgery. In cardiomyocytes, overexpression of ING3 caused an increase in ANP, BNP and β-MHC mRNA levels and cell surface area, while depletion of ING3 attenuated PE-induced cardiomyocyte hypertrophy. Mechanistically, we have demonstrated that overexpression of ING3 could inactivate the AMPK and activate the canonical p38 MAPK signaling. Remarkably, AMPK agonist AICAR or p38 MAPK inhibitor SB203580 abrogated ING3-induced hypertrophic response in cardiomyocytes. In summary, our data disclose a novel role of ING3 as an inducer of pathological cardiac hypertrophy, suggesting that silencing of ING3 may be explored as a potential therapeutic target in preventing cardiac hypertrophy.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Si
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China.
authors.forename: Suowen
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China. Electronic address: Liupq_sysu@163.com.
authors.forename: Peiqing
authors.initials: P
authors.lastname: Liu
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001012:Aorta, Abdominal / Q000473:pathology; D006332:Cardiomegaly; D002462:Cell Membrane / Q000378:metabolism; D007093:Imidazoles / Q000737:chemistry; D007545:Isoproterenol / Q000737:chemistry; D020935:MAP Kinase Signaling System; D008297:Male; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000166:cytology* / Q000378:metabolism; D010656:Phenylephrine / Q000737:chemistry; D010957:Plasmids / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: C000595580:ING3 protein, rat; D007093:Imidazoles; D011725:Pyridines; D025521:Tumor Suppressor Proteins; D000804:Angiotensin II; D010656:Phenylephrine; D048051:p38 Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D007545:Isoproterenol; C093642:SB 203580
keywords: AMPK; Cardiac hypertrophy; ING3; Signaling pathway; p38 MAPK