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Bone Morphogenic Protein-7 Contributes to Cerebral Ischemic Preconditioning Induced-Ischemic Tolerance by Activating p38 Mitogen-Activated Protein Kinase Signaling Pathway

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Abstract

Cerebral ischemic preconditioning (IPC), which refers to a transient and noninjurious ischemia is able to induce tolerance against the subsequent lethal ischemia, including ischemic stroke. We have previously reported that bone morphogenic protein-7 (BMP-7) contributes to the neuroprotective effects of IPC-induced ischemic tolerance, and thus ameliorates the following ischemia/reperfusion (I/R) injury in rats. Consequently, in the present study, we continued to explore the underlying regulatory mechanisms involved in BMP-7-mediated cerebral IPC in the rat model of ischemic tolerance. Male Wistar rats were preconditioned by 15-min middle cerebral artery occlusion (MCAO). After 2-day reperfusion, these animals were subjected to prolonged MCAO for 2 h. Our results showed that the phosphorylated p38 mitogen-activated protein kinase (MAPK) paralleling to BMP-7 was up-regulated by IPC in rat brain. Inactivation of p38 MAPK by pretreatment of SB203580, a p38 MAPK-specific suppressor, weakened the protective effect of IPC on CA1 neurons. Moreover, the enhanced phosphorylation of p38 MAPK induced by IPC was attenuated when the endogenous BMP-7 was inhibited by BMP-7 antagonist noggin. Besides, blockade of p38 MAPK signal transduction pathway via SB203580 abrogated the protective effects of exogenous BMP-7 against cerebral infraction. These present findings suggest that BMP-7 contributes to cerebral IPC-induced ischemic tolerance via activating p38 MAPK signaling pathway.

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References

  1. Jiang, B., W.Z. Wang, H. Chen, Z. Hong, Q.D. Yang, S.P. Wu, X.L. Du, and Q.J. Bao. 2006. Incidence and trends of stroke and its subtypes in China: results from three large cities. Stroke 37: 63–68.

    Article  PubMed  Google Scholar 

  2. Guo, J.M., A.J. Liu, and D.F. Su. 2010. Genetics of stroke. Acta Pharmacologica Sinica 31: 1055–1064.

    Article  CAS  PubMed  Google Scholar 

  3. Donnan, G.A., M. Fisher, M. Macleod, and S.M. Davis. 2008. Stroke. Lancet 371: 1612–1623.

    Article  CAS  PubMed  Google Scholar 

  4. Gibson, C.L. 2013. Cerebral ischemic stroke: is gender important? Journal of Cerebral Blood Flow and Metabolism 33: 1355–1361.

    Article  PubMed  Google Scholar 

  5. Sacco, R.L., and J.K. Liao. 2005. Drug insight: statins and stroke. Nature Clinical Practice Cardiovascular Medicine 2: 576–584.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. Johansen, F.F., H. Hasseldam, R.S. Rasmussen, A.S. Bisgaard, P.K. Bonfils, S.S. Poulsen, and J. Hansen-Schwartz. 2014. Drug-induced hypothermia as beneficial treatment before and after cerebral ischemia. Pathobiology 81: 42–52.

    Article  CAS  PubMed  Google Scholar 

  7. Iadecola, C., and J. Anrather. 2011. Stroke research at a crossroad: asking the brain for directions. Nature Neuroscience 14: 1363–1368.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Dirnagl, U., K. Becker, and A. Meisel. 2009. Preconditioning and tolerance against cerebral ischaemia: from experimental strategies to clinical use. Lancet Neurology 8: 398–412.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Kirino, T. 2002. Ischemic tolerance. Journal of Cerebral Blood Flow and Metabolism 22: 1283–1296.

    Article  PubMed  Google Scholar 

  10. Kang, Y., W.M. Liao, Z.H. Yuan, P.Y. Sheng, L.J. Zhang, X.W. Yuan, and L. Lei. 2007. In vitro and in vivo induction of bone formation based on adeno-associated virus-mediated BMP-7 gene therapy using human adipose-derived mesenchymal stem cells. Acta Pharmacologica Sinica 28: 839–849.

    Article  CAS  PubMed  Google Scholar 

  11. Radhakrishnan, R.S., G.L. Radhakrishnan, H.R. Radhakrishnan, H. Xue, S.D. Adams, S.D. Moore-Olufemi, M.T. Harting, C.S. Cox Jr., and B.C. Kone. 2008. Pretreatment with bone morphogenetic protein-7 (BMP-7) mimics ischemia preconditioning following intestinal ischemia/reperfusion injury in the intestine and liver. Shock 30: 532–536.

    Article  PubMed Central  PubMed  Google Scholar 

  12. Guan, J., H. Li, T. Lv, D. Chen, Y. Yuan, and S. Qu. 2013. Bone morphogenetic protein-7 (BMP-7) mediates ischemic preconditioning-induced ischemic tolerance via attenuating apoptosis in rat brain. Biochemical and Biophysical Research Communications 441: 560–566.

    Article  CAS  PubMed  Google Scholar 

  13. Roux, P.P., and J. Blenis. 2004. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiology and Molecular Biology Reviews 68: 320–344.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Zarubin, T., and J. Han. 2005. Activation and signaling of the p38 MAP kinase pathway. Cell Research 15: 11–18.

    Article  CAS  PubMed  Google Scholar 

  15. Ono, K., and J. Han. 2000. The p38 signal transduction pathway: activation and function. Cellular Signalling 12: 1–13.

    Article  CAS  PubMed  Google Scholar 

  16. Hu, M.C., D. Wasserman, S. Hartwig, and N.D. Rosenblum. 2004. p38MAPK acts in the BMP7-dependent stimulatory pathway during epithelial cell morphogenesis and is regulated by Smad1. Journal of Biological Chemistry 279: 12051–12059.

    Article  CAS  PubMed  Google Scholar 

  17. Motazed, R., P. Colville-Nash, J.T. Kwan, and M.E. Dockrell. 2008. BMP-7 and proximal tubule epithelial cells: activation of multiple signaling pathways reveals a novel anti-fibrotic mechanism. Pharmaceutical Research 25: 2440–2446.

    Article  CAS  PubMed  Google Scholar 

  18. Takahashi, M., F. Otsuka, T. Miyoshi, H. Otani, J. Goto, M. Yamashita, T. Ogura, H. Makino, and H. Doihara. 2008. Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation. Journal of Endocrinology 199: 445–455.

    Article  CAS  PubMed  Google Scholar 

  19. Elshaier, A.M., A.A. Hakimiyan, L. Rappoport, D.C. Rueger, and S. Chubinskaya. 2009. Effect of interleukin-1beta on osteogenic protein 1-induced signaling in adult human articular chondrocytes. Arthritis & Rheumatism 60: 143–154.

    Article  CAS  Google Scholar 

  20. Nishimura, M., T. Sugino, K. Nozaki, Y. Takagi, I. Hattori, J. Hayashi, N. Hashimoto, T. Moriguchi, and E. Nishida. 2003. Activation of p38 kinase in the gerbil hippocampus showing ischemic tolerance. Journal of Cerebral Blood Flow and Metabolism 23: 1052–1059.

    Article  CAS  PubMed  Google Scholar 

  21. Li, W., Y. Luo, F. Zhang, A.P. Signore, G.T. Gobbel, R.P. Simon, and J. Chen. 2006. Ischemic preconditioning in the rat brain enhances the repair of endogenous oxidative DNA damage by activating the base-excision repair pathway. Journal of Cerebral Blood Flow and Metabolism 26: 181–198.

    Article  PubMed  Google Scholar 

  22. Barancik, M., V. Bohacova, J. Kvackajova, S. Hudecova, O. Krizanova, and A. Breier. 2001. SB203580, a specific inhibitor of p38-MAPK pathway, is a new reversal agent of P-glycoprotein-mediated multidrug resistance. European Journal of Pharmaceutical Sciences 14: 29–36.

    Article  CAS  PubMed  Google Scholar 

  23. Groppe, J., J. Greenwald, E. Wiater, J. Rodriguez-Leon, A.N. Economides, W. Kwiatkowski, M. Affolter, W.W. Vale, J.C. Izpisua Belmonte, and S. Choe. 2002. Structural basis of BMP signalling inhibition by the cystine knot protein Noggin. Nature 420: 636–642.

    Article  CAS  PubMed  Google Scholar 

  24. Kato, H., Y. Liu, T. Araki, and K. Kogure. 1991. Temporal profile of the effects of pretreatment with brief cerebral ischemia on the neuronal damage following secondary ischemic insult in the gerbil: cumulative damage and protective effects. Brain Research 553: 238–242.

    Article  CAS  PubMed  Google Scholar 

  25. Gong, S.J., L.Y. Chen, M. Zhang, J.X. Gong, Y.X. Ma, J.M. Zhang, Y.J. Wang, Y.Y. Hu, X.C. Sun, W.B. Li, and Y. Zhang. 2012. Intermittent hypobaric hypoxia preconditioning induced brain ischemic tolerance by up-regulating glial glutamate transporter-1 in rats. Neurochemical Research 37: 527–537.

    Article  CAS  PubMed  Google Scholar 

  26. Lin, T.N., Y.Y. He, G. Wu, M. Khan, and C.Y. Hsu. 1993. Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke 24: 117–121.

    Article  CAS  PubMed  Google Scholar 

  27. Wagner, D.O., C. Sieber, R. Bhushan, J.H. Borgermann, D. Graf, and P. Knaus. 2010. BMPs: from bone to body morphogenetic proteins. Science Signaling 3:mr1.

    Google Scholar 

  28. Marais, E., S. Genade, B. Huisamen, J.G. Strijdom, J.A. Moolman, and A. Lochner. 2001. Activation of p38 MAPK induced by a multi-cycle ischaemic preconditioning protocol is associated with attenuated p38 MAPK activity during sustained ischaemia and reperfusion. J Journal of Molecular and Cellular Cardiology 33: 769–778.

    Article  CAS  Google Scholar 

  29. Dreixler, J.C., F.C. Barone, A.R. Shaikh, E. Du, and S. Roth. 2009. Mitogen-activated protein kinase p38alpha and retinal ischemic preconditioning. Experimental Eye Research 89: 782–790.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Weinbrenner, C., G.S. Liu, M.V. Cohen, and J.M. Downey. 1997. Phosphorylation of tyrosine 182 of p38 mitogen-activated protein kinase correlates with the protection of preconditioning in the rabbit heart. Journal of Molecular and Cellular Cardiology 29: 2383–2391.

    Article  CAS  PubMed  Google Scholar 

  31. Saurin, A.T., J.L. Martin, R.J. Heads, C. Foley, J.W. Mockridge, M.J. Wright, Y. Wang, and M.S. Marber. 2000. The role of differential activation of p38-mitogen-activated protein kinase in preconditioned ventricular myocytes. FASEB Journal 14: 2237–2246.

    Article  CAS  PubMed  Google Scholar 

  32. Kobayashi, M., I. Takeyoshi, D. Yoshinari, K. Matsumoto, and Y. Morishita. 2002. P38 mitogen-activated protein kinase inhibition attenuates ischemia-reperfusion injury of the rat liver. Surgery 131: 344–349.

    Article  PubMed  Google Scholar 

  33. Lin, S.Z., B.J. Hoffer, P. Kaplan, and Y. Wang. 1999. Osteogenic protein-1 protects against cerebral infarction induced by MCA ligation in adult rats. Stroke 30: 126–133.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Neurosurgery, Shengjing Hospital, China Medical University, 36 Sanhao Street, Shenyang, 110004, People’s Republic of China

    Junhong Guan, Tao Lv, Duo Chen, Ye Yuan & Shengtao Qu

  2. Department of Emergency Medicine, Shengjing Hospital, China Medical University, Shenyang, 110004, People’s Republic of China

    Han Li

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  1. Junhong Guan
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  3. Tao Lv
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Correspondence to Junhong Guan.

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Guan, J., Li, H., Lv, T. et al. Bone Morphogenic Protein-7 Contributes to Cerebral Ischemic Preconditioning Induced-Ischemic Tolerance by Activating p38 Mitogen-Activated Protein Kinase Signaling Pathway. Inflammation 37, 1289–1296 (2014). https://doi.org/10.1007/s10753-014-9856-7

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