Rapamycin protects cardiomyocytes against anoxia/reoxygenation injury by inducing autophagy through the PI3k/Akt pathway

  • Lu-qiao Wang (王路乔)
  • Xiao-shu Cheng (程晓曙)
  • Cha-hua Huang (黄茶花)
  • Bo Huang (黄 波)
  • Qian Liang (梁 茜)
Article
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Summary

The purpose of this study was to investigate the potential cardioprotection roles of Rapamycin in anoxia/reoxygenation (A/R) injury of cardiomyocytes through inducing autophagy, and the involvement of PI3k/Akt pathway. We employed simulated A/R of neonatal rat ventricular myocytes (NRVM) as an in vitro model of ischemial/reperfusion (I/R) injury to the heart. NRVM were pretreated with four different concentrations of Rapamycin (20, 50, 100, 150 μmol/L), and pretreated with 10 mmol/L 3-methyladenine (3MA) for inhibiting autophagy during A/R. Then, Western blot analysis was used to examine variation in the expression of LC3-II, LC3-I, Bim, caspase-3, p-PI3KI, PI3KI, p-Akt and Akt. In our model, Rapamycin had a preferential action on autophagy, increasing the expression of LC3-II/LC3-I, whereas decreasing the expression of Bim and caspase-3. Moreover, our results also demonstrated that Rapamycin inhibited the activation of p-PI3KI and enhanced the activation of p-Akt. It is concluded that Rapamycin has a cardioprotection effect by inducing autophagy in a concentration-dependent manner against apopotosis through PI3K/Akt signaling pathway during A/R in NRVM.

Key words

rapamycin autophagy anoxia/reoxygenation apoptosis 
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References

  1. 1.
    Murray CJ, Lopez AD. Alternate projections of mortality and disability by cause 1990–2020: global burden of disease study. Lancet, 1997,349(9064):1498–1504CrossRefPubMedGoogle Scholar
  2. 2.
    Gottlieb RA, Mentzer RJ. Autophagy: an affair of the heart. Heart Fail Rev, 2013,18(5):575–584.CrossRefPubMedCentralPubMedGoogle Scholar
  3. 3.
    Sabe AA, Elmadhun NY, Dalal RS, et al. Resveratrol regulates autophagy signaling in chronically ischemic myocardium. J Thorac Cardiovasc Surg, 2014,147(2):792–798, 798–799CrossRefPubMedCentralPubMedGoogle Scholar
  4. 4.
    Choi AM, Ryter SW, Levine B. Autophagy in human health and disease. N Engl J Med, 2013,368(7):1845–1846CrossRefPubMedGoogle Scholar
  5. 5.
    Matsui Y, Takagi H, Qu X, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res, 2007,100(6):914–922CrossRefPubMedGoogle Scholar
  6. 6.
    Takagi H, Matsui Y, Sadoshima J. The role of autophagy in mediating cell survival and death during ischemia and reperfusion in the heart. Antioxid Redox Signal, 2007,9(9):1373–1381CrossRefPubMedGoogle Scholar
  7. 7.
    Khan S, Salloum F, Das A, et al. Rapamycin confers preconditioning-like protection against ischemia-reperfusion injury in isolated mouse heart and cardiomyocytes. J Mol Cell Cardiol, 2006,41(2):256–264CrossRefPubMedGoogle Scholar
  8. 8.
    Ravikumar B, Vacher C, Berger Z, et al. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet, 2004,36(6):585–595CrossRefPubMedGoogle Scholar
  9. 9.
    Youle RJ, Strasser A. The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 2008,9(1):47–59CrossRefPubMedGoogle Scholar
  10. 10.
    Yang SS, Liu YB, Yu JB, et al. Rapamycin protects heart from ischemia/reperfusion injury independent of autophagy by activating PI3 kinase-Akt pathway and mitochondria K (ATP) channel. Pharmazie, 2010,65(10):760–765PubMedGoogle Scholar
  11. 11.
    Wang X, Dai Y, Ding Z, et al. Regulation of autophagy and apoptosis in response to angiotensin II in HL-1 cardiomyocytes. Biochem Biophys Res Commun, 2013,440(4):696–700CrossRefPubMedGoogle Scholar
  12. 12.
    Crow MT, Mani K, Nam YJ, et al. The mitochondrial death pathway and cardiac myocyte apoptosis. Circ Res, 2004,95(10):957–970CrossRefPubMedGoogle Scholar
  13. 13.
    Desagher S, Martinou JC. Mitochondria as the central control point of apoptosis. Trends Cell Biol, 2000,10(9): 369–377CrossRefPubMedGoogle Scholar
  14. 14.
    Hamacher-Brady A, Brady NR, Gottlieb RA. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem, 2006,281(40): 29776–29787CrossRefPubMedGoogle Scholar
  15. 15.
    Stennicke HR, Salvesen GS. Caspases-controlling intra-cellular signals by protease zymogen activation. Biochim Biophys Acta, 2000,1477(1):299–306CrossRefPubMedGoogle Scholar
  16. 16.
    Raphael J, Zuo Z, Abedat S, et al. Isoflurane preconditioning decreases myocardial infarction in rabbits via up-regulation of hypoxia inducible factor 1 that is mediated by mammalian target of rapamycin. Anesthesiology, 2008,108(3):415–425CrossRefPubMedGoogle Scholar
  17. 17.
    Tsang A, Hausenloy DJ, Mocanu MM, et al. Postconditioning: a form of “modified reperfusion” protects the myocardium by activating the phosphatidylinositol 3-kinase-Akt pathway. Circ Res, 2004,95(3):230–232CrossRefPubMedGoogle Scholar

Copyright information

© Huazhong University of Science and Technology and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Lu-qiao Wang (王路乔)
    • 1
    • 2
  • Xiao-shu Cheng (程晓曙)
    • 1
    • 2
  • Cha-hua Huang (黄茶花)
    • 1
  • Bo Huang (黄 波)
    • 3
  • Qian Liang (梁 茜)
    • 1
  1. 1.Jiangxi Key Laboratory of Molecular MedicineNanchang UniversityNanchangChina
  2. 2.Department of Cardiovascular MedicineNanchang UniversityNanchangChina
  3. 3.Department of Clinical Laboratorythe Second Affiliated Hospital of Nanchang UniversityNanchangChina

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