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Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress

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Abstract

Oxidative/nitrative stress plays an important role in myocardial ischemia/reperfusion (MI/R) injury. Notch1 participates in the regulation of cardiogenesis and cardiac response to hypertrophic stress, but the function of Notch1 signaling in MI/R has not been explored. This study aims to determine the role of Notch1 in MI/R, and investigate whether Notch1 confers cardioprotection. Notch1 specific small interfering RNA (siRNA, 20 μg) or Jagged1 (a Notch ligand, 12 μg) was delivered through intramyocardial injection. 48 h after injection, mice were subjected to 30 min of myocardial ischemia followed by 3 h (for cell apoptosis and oxidative/nitrative stress), 24 h (for infarct size and cardiac function), or 2 weeks (for cardiac fibrosis and function) of reperfusion. Cardiac-specific Notch1 knockdown resulted in significantly aggravated I/R injury, as evidenced by enlarged infarct size, depressed cardiac function, increased myocardial apoptosis and cardiac fibrosis. Downregulation of Notch1 increased expression of inducible NO synthase (iNOS) and gp91phox, enhanced the production of NO metabolites and superoxide, as well as their cytotoxic reaction product peroxynitrite. Moreover, Notch1 blockade also reduced phosphorylation of endothelial NO synthase (eNOS) and Akt, and increased expression of PTEN, a key phosphatase involved in the regulation of Akt phosphorylation. In addition, activation of Notch1 by Jagged1 or administration of peroxynitrite scavenger reduced production of peroxynitrite and attenuated MI/R injury. These data indicate that Notch1 signaling protects against MI/R injury partly though PTEN/Akt mediated anti-oxidative and anti-nitrative effects.

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Acknowledgments

Supported by Program for Chinese National Science Fund for Distinguished Young Scholars (Grant No. 81225001), New Century Excellent Talents in University (Grant No. NCET-11-0870), National Basic Research Program (973 Program) (Grant No. 9732013CB531200) and Chinese National Science Funds (Grants No. 81070676 and 81170186).

Conflict of interest

The authors have not disclosed any potential conflict of interest.

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Authors and Affiliations

  1. Department of Cardiology, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi’an, 710032, China

    Haifeng Pei, Qiujun Yu, Qiang Xue, Yunping Guo, Lu Sun, Zhibo Hong & Ling Tao

  2. Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, 15 Changlexi Road, Xi’an, 710032, China

    Yan Qu

  3. State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Xi’an, 710032, China

    Hua Han

  4. Center of Translational Medicine, Temple University School of Medicine, Philadelphia, PA, 19140, USA

    Erhe Gao

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  1. Haifeng Pei
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  9. Yan Qu
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  10. Ling Tao
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Corresponding authors

Correspondence to Yan Qu or Ling Tao.

Additional information

Haifeng Pei, Qiujun Yu and Qiang Xue contributed equally to this work.

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Pei, H., Yu, Q., Xue, Q. et al. Notch1 cardioprotection in myocardial ischemia/reperfusion involves reduction of oxidative/nitrative stress. Basic Res Cardiol 108, 373 (2013). https://doi.org/10.1007/s00395-013-0373-x

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  • DOI: https://doi.org/10.1007/s00395-013-0373-x

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