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Knockdown of KLF11 attenuates hypoxia/reoxygenation injury via JAK2/STAT3 signaling in H9c2

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Abstract

KLF11 is a Krüppel-like factor (KLF) family member, which plays a central role in cardiac hypertrophy and cerebrovascular protection during ischemic insults. However, the roles of KLF11 in hypoxia/reoxygenation (H/R) injury of rat cardiomyocytes H9c2 have not been elucidated. The aim of this study was to evaluate the effects of KLF11 on H/R injury and investigate the molecular mechanisms involved. Here, we found that KLF11 was increased following H/R and reached the highest level with 24 h hypoxia followed by 12 h reoxygenation. Moreover, we found that inhibition of KLF11 by small RNA suppressed cell apoptosis, the activity of caspase3, the expression of cleaved-caspase3 and cytochrome C in the cytoplasm and the damage of mitochondrial membrane induced by H/R in H9c2, suggesting that KLF11 silencing protects against H/R injury. In addition, we observed that knockdown of KLF11 elevated the expression of p-JAK2 and p-STAT3 in H9c2, and AG490, a selective inhibitor of JAK2/STAT3 abrogated the potential roles of KLF11 in cell apoptosis and mitochondrial damage. In aggregates, our results showed that depletion of KLF11 protected H9c2 against H/R injury through activating the JAK2/STAT3 signaling pathway, suggesting that KLF11 may be provide therapeutic targets for H/R or other heart diseases.

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References

  1. Gersh BJ, Sliwa K, Mayosi BM, Yusuf S (2010) Novel therapeutic concepts: the epidemic of cardiovascular disease in the developing world: global implications. Eur Heart J 31(6):642–648

    Article  PubMed  Google Scholar 

  2. Zweier JL, Talukder MH (2006) The role of oxidants and free radicals in reperfusion injury. Cardiovasc Res 70(2):181–190

    Article  CAS  PubMed  Google Scholar 

  3. Frank A, Bonney M, Bonney S, Weitzel L, Koeppen M, Eckle T (2012) Myocardial ischemia reperfusion injury from basic science to clinical bedside. In: Seminars in cardiothoracic and vascular anesthesia. SAGE Publications, pp 123–132

  4. Hausenloy DJ, Yellon DM (2013) Myocardial ischemia–reperfusion injury: a neglected therapeutic target. J Clin investig 123(1):92–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Stark GR, Darnell JE (2012) The JAK-STAT pathway at twenty. Immunity 36(4):503–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Levy DE, Darnell J (2002) Stats: transcriptional control and biological impact. Nat Rev Mol Cell Biol 3(9):651–662

    Article  CAS  PubMed  Google Scholar 

  7. Barry SP, Townsend PA, Latchman DS, Stephanou A (2007) Role of the JAK–STAT pathway in myocardial injury. Trends Mol Med 13(2):82–89

    Article  CAS  PubMed  Google Scholar 

  8. Cittadini A, Monti MG, Iaccarino G, Castiello MC, Baldi A, Bossone E, Longobardi S, Marra AM, Petrillo V, Saldamarco L (2012) SOCS1 gene transfer accelerates the transition to heart failure through the inhibition of the gp130/JAK/STAT pathway. Cardiovasc Res 96(3):381–390

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. You L, Li L, Xu Q, Ren J, Zhang F (2011) Postconditioning reduces infarct size and cardiac myocyte apoptosis via the opioid receptor and JAK-STAT signaling pathway. Mol Biol Rep 38(1):437–443

    Article  CAS  PubMed  Google Scholar 

  10. Haghikia A, Ricke-Hoch M, Stapel B, Gorst I, Hilfiker-Kleiner D (2014) STAT3, a key regulator of cell-to-cell communication in the heart. Cardiovasc Res 102(2):281–289

    Article  CAS  PubMed  Google Scholar 

  11. McConnell BB, Yang VW (2010) Mammalian Krüppel-like factors in health and diseases. Physiol Rev 90(4):1337–1381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Pearson R, Fleetwood J, Eaton S, Crossley M, Bao S (2008) Krüppel-like transcription factors: a functional family. Int J Biochem Cell Biol 40(10):1996–2001

    Article  CAS  PubMed  Google Scholar 

  13. Yin K-J, Fan Y, Hamblin M, Zhang J, Zhu T, Li S, Hawse JR, Subramaniam M, Song C-Z, Urrutia R (2013) KLF11 mediates PPARγ cerebrovascular protection in ischaemic stroke. Brain 136(4):1274–1287

    Article  PubMed  PubMed Central  Google Scholar 

  14. Zhang H, Chen Q, Yang M, Zhu B, Cui Y, Xue Y, Gong N, Cui A, Wang M, Shen L (2013) Mouse KLF11 regulates hepatic lipid metabolism. J Hepatol 58(4):763–770

    Article  CAS  PubMed  Google Scholar 

  15. Mathison A, Escande C, Calvo E, Seo S, White T, Salmonson A, Faubion WA Jr, Buttar N, Iovanna J, Lomberk G (2015) Phenotypic characterization of mice carrying homozygous deletion of KLF11, a gene in which mutations cause human neonatal and MODY VII diabetes. Endocrinology 156(10):3581–3595

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Zheng Y, Kong Y, Li F (2014) Krüppel-like transcription factor 11 (KLF11) overexpression inhibits cardiac hypertrophy and fibrosis in mice. Biochem Biophys Res Commun 443(2):683–688

    Article  CAS  PubMed  Google Scholar 

  17. Yue R, Hu H, Yiu KH, Luo T, Zhou Z, Xu L, Zhang S, Li K, Yu Z (2012) Lycopene protects against hypoxia/reoxygenation-induced apoptosis by preventing mitochondrial dysfunction in primary neonatal mouse cardiomyocytes. PloS one 7(11):e50778

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Haghikia A, Stapel B, Hoch M, Hilfiker-Kleiner D (2011) STAT3 and cardiac remodeling. Heart Fail Rev 16(1):35–47

    Article  CAS  PubMed  Google Scholar 

  19. Thind GS, Agrawal PR, Hirsh B, Saravolatz L, Chen-Scarabelli C, Narula J, Scarabelli TM (2015) Mechanisms of myocardial ischemia–reperfusion injury and the cytoprotective role of minocycline: scope and limitations. Future Cardiol 11(1):61–76

    Article  CAS  PubMed  Google Scholar 

  20. Fan Y, Guo Y, Zhang J, Subramaniam M, Song C-Z, Urrutia R, Chen YE (2012) Krüppel-like factor-11, a transcription factor involved in diabetes mellitus, suppresses endothelial cell activation via the nuclear factor-κB signaling pathway. Arterioscler Thromb Vasc Biol 32(12):2981–2988

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gohla G, Krieglstein K, Spittau B (2008) Tieg3/Klf11 induces apoptosis in OLI-neu cells and enhances the TGF-βeu cells and enhances the TGF-β signaling pathway by transcriptional repression of Smad7. J Cell Biochem 104(3):850–861

    Article  CAS  PubMed  Google Scholar 

  22. Wang Z, Spittau B, Behrendt M, Peters B, Krieglstein K (2007) Human TIEG2/KLF11 induces oligodendroglial cell death by downregulation of Bcl-XL expression. J Neural transm 114(7):867–875

    Article  CAS  PubMed  Google Scholar 

  23. Mathison A, Grzenda A, Lomberk G, Velez G, Buttar N, Tietz P, Hendrickson H, Liebl A, Xiong YY, Gores G (2013) Role for Kruppel-like transcription factor 11 in mesenchymal cell function and fibrosis. PloS one 8:e75311

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Loft A, Forss I, Siersbæk MS, Schmidt SF, Larsen A-SB, Madsen JGS, Pisani DF, Nielsen R, Aagaard MM, Mathison A (2014) Browning of human adipocytes requires KLF11 and reprogramming of PPARγ superenhancers. Genes Dev 29(1):7–22

    Article  PubMed  Google Scholar 

  25. Babbitt SE, Sutherland MC, San Francisco B, Mendez DL, Kranz RG (2015) Mitochondrial cytochrome c biogenesis: no longer an enigma. Trends Biochem Sci 40(8):446–455

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Bolli R, Dawn B, Xuan Y-T (2003) Role of the JAK–STAT pathway in protection against myocardial ischemia/reperfusion injury. Trends Cardiovasc Med 13(2):72–79

    Article  CAS  PubMed  Google Scholar 

  27. Freitas MCS, Uchida Y, Zhao D, Ke B, Busuttil RW, Kupiec-Weglinski JW (2010) Blockade of Janus kinase-2 signaling ameliorates mouse liver damage due to ischemia and reperfusion. Liver. Transplantation 16(5):600–610

    Google Scholar 

  28. Wang Y, Wang D, Zhang L, Ye F, Li M, Wen K (2016) Role of JAK-STAT pathway in reducing cardiomyocytes hypoxia/reoxygenation injury induced by S1P postconditioning. Eur J Pharmacol 784:129–136

    Article  CAS  PubMed  Google Scholar 

  29. Li L, Li M, Li Y, Sun W, Wang Y, Bai S et al (2016) Exogenous H2S contributes to recovery of ischemic post-conditioning-induced cardioprotection by decrease of ROS level via down-regulation of NF-κB and JAK2-STAT3 pathways in the aging cardiomyocytes. Cell Biosci 6(1):1

    Article  Google Scholar 

  30. Puigdecanet E, Espinet B, Lozano J, Sumoy L, Bellosillo B, Arenillas L, Alvarez-Larran A, Sole F, Serrano S, Besses C (2008) Gene expression profiling distinguishes JAK2V617F-negative from JAK2V617F-positive patients in essential thrombocythemia. Leukemia 22(7):1368–1376

    Article  CAS  PubMed  Google Scholar 

  31. Tetreault M-P, Alrabaa R, McGeehan M, Katz JP (2012) Krüppel-like factor 5 protects against murine colitis and activates JAK-STAT signaling in vivo. PloS one 7(5):e38338

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Cardiology, The First Affiliated Hospital of China Medical University, Shenyang, 110001, People’s Republic of China

    Yang Li, Jian Li, Minghui Zhang & Bo Yu

  2. Department of Cardiology, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121001, People’s Republic of China

    Xiaojing Shi

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  1. Yang Li
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  2. Xiaojing Shi
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  3. Jian Li
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  4. Minghui Zhang
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  5. Bo Yu
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Correspondence to Bo Yu.

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Li, Y., Shi, X., Li, J. et al. Knockdown of KLF11 attenuates hypoxia/reoxygenation injury via JAK2/STAT3 signaling in H9c2. Apoptosis 22, 510–518 (2017). https://doi.org/10.1007/s10495-016-1327-1

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  • DOI: https://doi.org/10.1007/s10495-016-1327-1

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