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Original Article

Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload

Xiaodi Wang, Wen Chen, Jie Zhang, Aiman Khan, Liangpeng Li, Fuhua Huang, Zhibing Qiu, Liming Wang, Xin Chen
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https://doi.org/10.1161/HYPERTENSIONAHA.116.08581
Hypertension. 2017;HYPERTENSIONAHA.116.08581
Originally published April 3, 2017
Xiaodi Wang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Wen Chen
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Jie Zhang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Aiman Khan
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Liangpeng Li
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Fuhua Huang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Zhibing Qiu
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Liming Wang
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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Xin Chen
From the Department of Thoracic and Cardiovascular Surgery, Nanjing First Hospital, Nanjing Medical University, Jiangsu, People’s Republic of China.
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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.

  • ADAMTS2
  • heart failure
  • hypertrophy
  • mouse
  • transgene
  • Received October 15, 2016.
  • Revision received October 29, 2016.
  • Accepted March 4, 2017.
  • © 2017 American Heart Association, Inc.
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    Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload
    Xiaodi Wang, Wen Chen, Jie Zhang, Aiman Khan, Liangpeng Li, Fuhua Huang, Zhibing Qiu, Liming Wang and Xin Chen
    Hypertension. 2017;HYPERTENSIONAHA.116.08581, originally published April 3, 2017
    https://doi.org/10.1161/HYPERTENSIONAHA.116.08581

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    Critical Role of ADAMTS2 (A Disintegrin and Metalloproteinase With Thrombospondin Motifs 2) in Cardiac Hypertrophy Induced by Pressure Overload
    Xiaodi Wang, Wen Chen, Jie Zhang, Aiman Khan, Liangpeng Li, Fuhua Huang, Zhibing Qiu, Liming Wang and Xin Chen
    Hypertension. 2017;HYPERTENSIONAHA.116.08581, originally published April 3, 2017
    https://doi.org/10.1161/HYPERTENSIONAHA.116.08581
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