title: Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload.
abstract: ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) is recognized as a metalloproteinase that promotes the cleavage of amino propeptides of types I, II, III, and V procollagens. However, the role of ADAMTS2 in the heart has not yet been defined. Herein, we observed the upregulated expression of ADAMTS2 in failing human hearts and hypertrophic murine hearts. Mice lacking ADAMTS2 display exacerbated cardiac hypertrophy on pressure overload-induced hypertrophic response, whereas mice with cardiac-specific overexpression of ADAMTS2 display alleviation of this detrimental phenotype. Consistent with these results, in vitro loss or gain of function experiments in neonatal rat cardiomyocytes confirmed that ADAMTS2 negatively regulates cardiomyocyte hypertrophy in response to Ang II. Mechanistically, blockage of the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)-dependent signaling pathway with specific inhibitors both in vivo and in vitro could rescue the aggravated hypertrophic response to the loss of ADAMTS2. Collectively, we propose that ADAMTS2 regulates the hypertrophic response through inhibiting the activation of the PI3K/AKT-dependent signaling pathway. Because ADAMTS2 is an extracellular protein, it could be effectively manipulated using pharmacological means to modulate cardiac hypertrophy.
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Xiaodi
authors.initials: X
authors.lastname: Wang
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Wen
authors.initials: W
authors.lastname: Chen
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Aiman
authors.initials: A
authors.lastname: Khan
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Liangpeng
authors.initials: L
authors.lastname: Li
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Fuhua
authors.initials: F
authors.lastname: Huang
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Zhibing
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China.
authors.forename: Liming
authors.initials: L
authors.lastname: Wang
authors.affiliation: From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People's Republic of China. stevecx@njmu.edu.cn.
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001707:Biopsy, Needle; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D004195:Disease Models, Animal; D019483:Disintegrins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D045726:Metalloproteases / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics*; D019699:Thrombospondins / Q000235:genetics*; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D018487:Ventricular Dysfunction, Left / Q000235:genetics / Q000473:pathology; D020257:Ventricular Remodeling / Q000235:genetics; D000099262:Thrombospondin 2
chemical_list: D000071096:ADAMTS Proteins; D000804:Angiotensin II; D019483:Disintegrins; D045726:Metalloproteases; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D019699:Thrombospondins; D000099262:Thrombospondin 2; C000609307:ADAMTS2 protein, human; C000609308:Adamts2 protein, mouse
keywords: ADAMTS2; heart failure; hypertrophy; mouse; transgene