Skip to main content
SpringerLink
Log in

Hypoxic preconditioning up-regulates DJ-1 protein expression in rat heart-derived H9c2 cells through the activation of extracellular-regulated kinase 1/2 pathway

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Myocardial preconditioning is a powerful phenomenon that can attenuate ischemia/reperfusion-induced oxidant stress and elicit delayed cardioprotection. Its mechanisms involve activation of intracellular signaling pathways and up-regulation of the protective antioxidant proteins. DJ-1 protein, as a multifunctional intracellular protein, plays an important role in attenuating oxidant stress and promoting cell survival. In the present study, we investigated whether DJ-1 is up-regulated during the late phase of hypoxic preconditioning (HP) and the up-regulation of DJ-1 is mediated by extracellular-regulated kinase 1/2 (ERK1/2) signaling pathway. Rat heart-derived H9c2 cells were exposed to HP. Twenty-four hours later cells were subjected to hypoxia/reoxygenation (H/R) and then cell viability, lactate dehydrogenase (LDH), intracellular reactive oxygen species (ROS), ERK1/2 phosphorylation, and DJ-1 protein were measured appropriately. The results showed that HP efficiently attenuated H/R-induced viability loss and LDH leakage. In addition, HP promoted ERK1/2 activation, up-regulated DJ-1 protein expression, inhibited H/R induced the elevation of ROS. However, when ERK1/2 phosphorylation was specifically inhibited by U0126, the increase in DJ-1 expression occurring during HP was almost completely abolished and, as a result, the delayed cardioprotection induced by HP was abolished, and the inhibitory effect of HP on H/R-induced oxidant stress was also reversed. Furthermore, knocking down DJ-1 by siRNA attenuated the delayed cardioprotection induced by HP. Our data indicate that HP can up-regulate DJ-1 protein expression through the ERK1/2-dependent signaling pathway. Importantly, DJ-1 might be involved in the delayed cardioprotective effect of HP against H/R injury.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  1. Murry CE, Jennings RB, Reimer KA (1986) Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation 74:1124–1136

    Article  PubMed  CAS  Google Scholar 

  2. Kuzuya T, Hoshida S, Yamashita N, Fuji H, Oe H, Hori M, Kamada T, Tada M (1993) Delayed effects of sublethal ischemia on the acquisition of tolerance to ischemia. Circ Res 72:1293–1299

    Article  PubMed  CAS  Google Scholar 

  3. Bolli R (2000) The late phase of preconditioning. Circ Res 87:972–983

    Article  PubMed  CAS  Google Scholar 

  4. Bolli R (1996) The early and late phases of preconditioning against myocardial stunning and the essential role of oxyradicals in the late phase: an overview. Basic Res Cardiol 91:57–63

    Article  PubMed  CAS  Google Scholar 

  5. Rizvi A, Tang XL, Qiu Y, Xuan YT, Takano H, Jadoon AK, Bolli R (1999) Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning. Am J Physiol 277:H874–H884

    PubMed  CAS  Google Scholar 

  6. Vanden Hoek T, Becker LB, Shao ZH, Li CQ, Schumacker PT (2000) Preconditioning in cardiomyocytes protects by attenuating oxidant stress at reperfusion. Circ Res 86:541–548

    Article  PubMed  CAS  Google Scholar 

  7. Morihira M, Hasebe N, Baljinnyam E, Sumitomo K, Matsusaka T, Izawa K, Fujino T, Fukuzawa J, Kikuchi K (2006) Ischemic preconditioning enhances scavenging activity of reactive oxygen species and diminishes transmural difference of infarct size. Am J Physiol Heart Circ Physiol 290:H577–H583. doi:10.1152/ajpheart.00817.2004

    Article  PubMed  CAS  Google Scholar 

  8. Hoshida S, Yamashita N, Otsu K, Hori M (2002) The importance of manganese superoxide dismutase in delayed preconditioning: involvement of reactive oxygen species and cytokines. Cardiovasc Res 55:495–505

    Article  PubMed  CAS  Google Scholar 

  9. Shinmura K, Bolli R, Liu SQ, Tang XL, Kodani E, Xuan YT, Srivastava S, Bhatnagar A (2002) Aldose reductase is an obligatory mediator of the late phase of ischemic preconditioning. Circ Res 91:240–246

    Article  PubMed  CAS  Google Scholar 

  10. Jancso G, Cserepes B, Gasz B, Benko L, Borsiczky B, Ferenc A, Kurthy M, Racz B, Lantos J, Gal J, Arato E, Sinayc L, Weber G, Roth E (2007) Expression and protective role of heme oxygenase-1 in delayed myocardial preconditioning. Ann N Y Acad Sci 1095:251–261. doi:10.1196/annals.1397.029

    Article  PubMed  CAS  Google Scholar 

  11. Nagakubo D, Taira T, Kitaura H, Ikeda M, Tamai K, Iguchi-Ariga SM, Ariga H (1997) DJ-1, a novel oncogene which transforms mouse NIH3T3 cells in cooperation with ras. Biochem Biophys Res Commun 231:509–513. doi:10.1006/bbrc.1997.6132

    Article  PubMed  CAS  Google Scholar 

  12. Lev N, Ickowicz D, Barhum Y, Lev S, Melamed E, Offen D (2009) DJ-1 protects against dopamine toxicity. J Neural Transm 116:151–160. doi:10.1007/s00702-008-0134-4

    Article  PubMed  CAS  Google Scholar 

  13. Lev N, Ickowicz D, Melamed E, Offen D (2008) Oxidative insults induce DJ-1 upregulation and redistribution: implications for neuroprotection. Neurotoxicology 29:397–405. doi:10.1016/j.neuro.2008.01.007

    Article  PubMed  CAS  Google Scholar 

  14. Taira T, Saito Y, Niki T, Iguchi-Ariga SM, Takahashi K, Ariga H (2004) DJ-1 has a role in antioxidative stress to prevent cell death. EMBO Rep 5:213–218. doi:10.1038/sj.embor.7400074

    Article  PubMed  CAS  Google Scholar 

  15. Zhou W, Freed CR (2005) DJ-1 up-regulates glutathione synthesis during oxidative stress and inhibits A53T alpha-synuclein toxicity. J Biol Chem 280:43150–43158. doi:10.1074/jbc.M507124200

    Article  PubMed  CAS  Google Scholar 

  16. Kim RH, Smith PD, Aleyasin H, Hayley S, Mount MP, Pownall S, Wakeham A, You-Ten AJ, Kalia SK, Horne P, Westaway D, Lozano AM, Anisman H, Park DS, Mak TW (2005) Hypersensitivity of DJ-1-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine (MPTP) and oxidative stress. Proc Natl Acad Sci USA 102:5215–5220. doi:10.1073/pnas.0501282102

    Article  PubMed  CAS  Google Scholar 

  17. Martinat C, Shendelman S, Jonason A, Leete T, Beal MF, Yang L, Floss T, Abeliovich A (2004) Sensitivity to oxidative stress in DJ-1-deficient dopamine neurons: an ES-derived cell model of primary Parkinsonism. PLoS Biol 2:e327. doi:10.1371/journal.pbio.0020327

    Article  PubMed  Google Scholar 

  18. Yokota T, Sugawara K, Ito K, Takahashi R, Ariga H, Mizusawa H (2003) Down regulation of DJ-1 enhances cell death by oxidative stress, ER stress, and proteasome inhibition. Biochem Biophys Res Commun 312:1342–1348

    Article  PubMed  CAS  Google Scholar 

  19. Yanagisawa D, Kitamura Y, Inden M, Takata K, Taniguchi T, Morikawa S, Morita M, Inubushi T, Tooyama I, Taira T, Iguchi-Ariga SM, Akaike A, Ariga H (2008) DJ-1 protects against neurodegeneration caused by focal cerebral ischemia and reperfusion in rats. J Cereb Blood Flow Metab 28:563–578. doi:10.1038/sj.jcbfm.9600553

    Article  PubMed  CAS  Google Scholar 

  20. Ping P, Zhang J, Cao X, Li RC, Kong D, Tang XL, Qiu Y, Manchikalapudi S, Auchampach JA, Black RG, Bolli R (1999) PKC-dependent activation of p44/p42 MAPKs during myocardial ischemia-reperfusion in conscious rabbits. Am J Physiol 276:H1468–H1481

    PubMed  CAS  Google Scholar 

  21. Xuan YT, Tang XL, Banerjee S, Takano H, Li RC, Han H, Qiu Y, Li JJ, Bolli R (1999) Nuclear factor-kappaB plays an essential role in the late phase of ischemic preconditioning in conscious rabbits. Circ Res 84:1095–1109

    Article  PubMed  CAS  Google Scholar 

  22. Huang YF, Gong KZ, Zhang ZG (2003) [Different roles of ERK(1/2) and p38 MAPK(alpha/beta) in cellular signaling during cardiomyocyte anoxia preconditioning]. Sheng Li Xue Bao 55:454–458

    PubMed  CAS  Google Scholar 

  23. Pesant M, Sueur S, Dutartre P, Tallandier M, Grimaldi PA, Rochette L and Connat JL (2006) Peroxisome proliferator-activated receptor delta (PPARdelta) activation protects H9c2 cardiomyoblasts from oxidative stress-induced apoptosis. Cardiovasc Res 69:440–449. doi:10.1016/j.cardiores.2005.10.019

    Google Scholar 

  24. Jiao JD, Garg V, Yang B, Hu K (2008) Novel functional role of heat shock protein 90 in ATP-sensitive K+ channel-mediated hypoxic preconditioning. Cardiovasc Res 77:126–133. doi:10.1093/cvr/cvm028

    Article  PubMed  CAS  Google Scholar 

  25. Clements CM, McNally RS, Conti BJ, Mak TW, Ting JP (2006) DJ-1, a cancer- and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proc Natl Acad Sci USA 103:15091–15096. doi:10.1073/pnas.0607260103

    Article  PubMed  CAS  Google Scholar 

  26. Zhong N, Xu J (2008) Synergistic activation of the human MnSOD promoter by DJ-1 and PGC-1alpha: regulation by SUMOylation and oxidation. Hum Mol Genet 17:3357–3367. doi:10.1093/hmg/ddn230

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the Natural Scientific Foundation of China (No. 81060022) and the Natural Scientific Foundation of Jiangxi Province (No. 2010GZY0220).

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Pharmacology & Molecular Therapeutics, School of Pharmaceutical Science, Nanchang University, Nanchang, 330006, People’s Republic of China

    Hai-Shan Lu, He-Ping Chen, Song Wang, Hai-Hong Yu, Xiao-Shan Huang, Qi-Ren Huang & Ming He

Authors
  1. Hai-Shan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. He-Ping Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Song Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hai-Hong Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xiao-Shan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qi-Ren Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ming He
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to He-Ping Chen.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lu, HS., Chen, HP., Wang, S. et al. Hypoxic preconditioning up-regulates DJ-1 protein expression in rat heart-derived H9c2 cells through the activation of extracellular-regulated kinase 1/2 pathway. Mol Cell Biochem 370, 231–240 (2012). https://doi.org/10.1007/s11010-012-1414-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-012-1414-8

Keywords

Search

Navigation