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Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling

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Abstract

Berberine (BBR) confers cardioprotective effect against myocardial ischemia reperfusion injury (MI/RI). Activation of Notch1/Hairy and enhancer of split 1 (Hes1) signaling also reduces MI/RI. We hypothesize that BBR may protect against MI/RI by modulating Notch1/Hes1-Phosphatase and tensin homolog deleted on chromosome ten (PTEN)/Akt signaling. In this study, male Sprague–Dawley rats were exposed to BBR treatment (200 mg/kg/d) for 2 weeks and then subjected to MI/RI. BBR significantly improved cardiac function recovery and decreased myocardial apoptosis, infarct size, serum creatine kinase and lactate dehydrogenase levels. Furthermore, in cultured H9c2 cardiomyocytes, BBR (50 μmol/L) attenuated simulated ischemia/reperfusion-induced myocardial apoptosis. Both in vivo and in vitro study showed that BBR treatment up-regulates Notch1 intracellular domain, Hes1, Bcl-2 expression and p-Akt/Akt ratio, down-regulates Bax Caspase-3 and cleaved Caspase-3 expression. However, the anti-apoptotic effect conferred by BBR was blocked by Notch1 siRNA, Hes1 siRNA or LY294002 (the specific inhibitor of Akt signaling) in the cultured cardiomyocytes. In summary, our results demonstrate that BBR treatment attenuates MI/RI by modulating Notch1/Hes1-PTEN/Akt signaling.

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Acknowledgments

The work presented here was carried out in collaboration between all authors. Shiqiang Yu and Weixun Duan defined the research theme and revised the manuscript critically. Liming Yu, Feijiang Li and Guolong Zhao designed methods and experiments, carried out the laboratory experiments and wrote the paper. Yang Yang, Zhenxiao Jin, Mengen Zhai, Wenjun Yu, Lin Zhao and Wensheng Chen collected and analyzed the data, interpreted the results. The authors thank Buying Li, Xiaowu Wang and Yanyan Ma, Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, for technical support in western blot and cell culture. This study was supported by grants from the National Natural Science Foundation of China (81470415, 81470411, 81270170) and the Natural Science Foundation of Shannxi Province (2014JM4106).

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The authors declare that they have no conflict of interest.

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    Authors and Affiliations

    1. Department of Cardiovascular Surgery, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, 710032, China

      Liming Yu, Yang Yang, Zhenxiao Jin, Mengen Zhai, Lin Zhao, Wensheng Chen, Weixun Duan & Shiqiang Yu

    2. Department of Biomedical Engineering, The Fourth Military Medical University, 169 Changle West Road, Xi’an, 710032, China

      Feijiang Li & Yang Yang

    3. Department of Cardiovascular Surgery, General Hospital, Ningxia Medical University, 804 Shengli South Street, Yinchuan, 750004, China

      Guolong Zhao

    4. Department of Cardiology, Xijing Hospital, The Fourth Military Medical University, 127 Changle West Road, Xi’an, 710032, China

      Wenjun Yu

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    1. Liming Yu
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    Correspondence to Weixun Duan or Shiqiang Yu.

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    Liming Yu, Feijiang Li and Guolong Zhao contributed equally to this study.

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    Yu, L., Li, F., Zhao, G. et al. Protective effect of berberine against myocardial ischemia reperfusion injury: role of Notch1/Hes1-PTEN/Akt signaling. Apoptosis 20, 796–810 (2015). https://doi.org/10.1007/s10495-015-1122-4

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