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Cardiomyocyte dimethylarginine dimethylaminohydrolase1 attenuates left-ventricular remodeling after acute myocardial infarction: involvement in oxidative stress and apoptosis

  • Lei Hou
  • Junjie Guo
  • Feng Xu
  • Xinyu Weng
  • Wenhui Yue
  • Junbo Ge
Original Contribution
  • 208 Downloads

Abstract

Asymmetric dimethylarginine (ADMA) is a risk factor for heart diseases. Dimethylarginine dimethylaminohydrolase (DDAH) enzymes are key proteins for ADMA degradation. Endothelial DDAH1 is a vital regulator of angiogenesis. DDAH1 is also expressed in cardiomyocytes. However, the role of DDAH1 in cardiomyocytes needs further clarification. Herein, we used an inducible cardiac-specific DDAH1 knockdown mouse (cardiac DDAH1−/−) to investigate the role of cardiomyocyte DDAH1 in left-ventricular (LV) remodeling after acute myocardial infarction (AMI). DDAH1flox/flox and α-MHCMerCreMer mice were used to generate cardiac DDAH1−/− mice. Deletion of DDAH1 in cardiomyocytes was confirmed by Western blotting. No significant differences were observed in plasma ADMA levels and LV function between cardiac DDAH1−/− mice and control mice. Cardiac DDAH1−/− mice showed aggravated LV remodeling 4 weeks after AMI, as demonstrated by a large infarct area and impaired LV function. The rate of cardiomyocyte apoptosis and level of oxidative stress were higher in the LV tissue of cardiac DDAH1−/− mice than in that of control mice. However, treatment of cardiomyocytes with exogenous ADMA had no effect on reactive oxygen species (ROS) levels or apoptosis sensitivity. Cardiac DDAH1−/− LV tissue showed downregulated superoxide dismutase2 (SOD2) expression, and treatment of DDAH1−/− cardiomyocytes with the SOD mimic tempol significantly attenuated apoptosis and ROS levels under hypoxic conditions. Tempol administration also attenuated oxidative stress and apoptosis in cardiac DDAH1−/− LV tissue and partially alleviated LV remodeling after AMI. DDAH1 in cardiomyocytes plays a vital role in attenuating LV remodeling after AMI by regulating intracellular ROS levels and apoptosis sensitivity via a SOD2-dependent pathway.

Keywords

Dimethylarginine dimethylaminohydrolase Acute myocardial infarction Left-ventricular remodeling Apoptosis Reactive oxygen species 

Notes

Acknowledgements

We thank Prof. Professor Yinjie Chen from the University of Minnesota for kindly offering DDAH1−/− mice and valued advice for this study.

Funding

This study was supported by research Grants 81770254, 81600308 from National Natural Science Foundation of China.

Compliance with ethical standards

Conflict of interest

All authors declare that they have no competing interests.

Supplementary material

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Supplementary material 1 (DOCX 12 kb)
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Supplementary material 2 (TIFF 11,835 kb)
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Supplementary material 3 (TIFF 9534 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  • Lei Hou
    • 1
  • Junjie Guo
    • 2
  • Feng Xu
    • 3
  • Xinyu Weng
    • 1
  • Wenhui Yue
    • 4
  • Junbo Ge
    • 1
  1. 1.Department of CardiologyShanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan UniversityShanghaiChina
  2. 2.Department of CardiologyThe Affiliated Hospital of Qingdao UniversityQingdaoChina
  3. 3.Scientific Research DepartmentShanghai Ninth People’s Hospital, Shanghai Jiao Tong University, School of MedicineShanghaiChina
  4. 4.Department of CardiologyPan-Vascular Research Institute, Shanghai Tenth People’s Hospital, Tongji University School of MedicineShanghaiChina

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