Skip to main content

Advertisement

SpringerLink
Log in

The protective microRNA-199a-5p-mediated unfolded protein response in hypoxic cardiomyocytes is regulated by STAT3 pathway

  • Original Article
  • Published:
Journal of Physiology and Biochemistry Aims and scope Submit manuscript

Abstract

The protective effects of downregulated miR-199a-5p on ischemic and hypoxic cardiomyocytes were well recognized, but the underlying mechanism of inhibited miR-199a-5p is not yet clear. The present study explored the relationship between enhanced signal transducer and activator of transcription 3 (STAT3) signaling and lowered production of miR-199a-5p in hypoxic cardiomyocytes. This study firstly found the correlation between elevated interleukin (IL)-6 and IL-11, as well as subsequent STAT3 signaling activation and the downregulation of miR-199a-5p in hypoxic myocardial samples from children with congenital heart disease. Then, using model of hypoxic mice and the intervention of phosphorylated STAT3 (pSTAT3), it was observed that pSTAT3 affected the expression of miR-199a-5p and modulated the expression of its target genes, including endoplasmic reticulum stress (ERS)-related activating transcription factor 6 (ATF6) and 78 kDa glucose-regulated protein (GRP78). Further observation revealed that the pSTAT3 signal in cardiac tissue could affect the expression of pri-miR-199a-2, a precursor of miR-199a-5p. And the chromatin immunoprecipitation (ChIP) assay also confirmed that pSTAT3 could bind to the promoter region of miR-199a-2 gene, which is more significant under hypoxic conditions. In conclusion, the activation of STAT3 signaling in cardiomyocytes during chronic hypoxia leads to downregulation of miR-199a-5p, which promotes the expression of many downstream target genes. This is an important pathway in the adaptive protection mechanism of myocardium during hypoxia.

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

Similar content being viewed by others

References

  1. Azzouzi HE, Leptidis S, Doevendans PA, De Windt LJ (2015) HypoxamiRs: regulators of cardiac hypoxia and energy metabolism. Trends Endocrinol Metab 26(9):502–508. https://doi.org/10.1016/j.tem.2015.06.008

    Article  CAS  PubMed  Google Scholar 

  2. Dai BB, Meng JR, Peyton M, Girard L, Bornmann WG, Ji L, Minna JD, Fang BL, Roth JA (2011) STAT3 mediates resistance to MEK inhibitor through MicroRNA miR-17. Cancer Res 71(10):3658–3668. https://doi.org/10.1158/0008-5472.CAN-10-3647

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dai BH, Geng L, Wang Y, Sui CJ, Xie F, Shen RX, Shen WF, Yang JM (2013) microRNA-199a-5p protects hepatocytes from bile acid-induced sustained endoplasmic reticulum stress. Cell Death Dis 4:e604. https://doi.org/10.1038/cddis.2013.134

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Das A, Salloum FN, Durrant D, Ockaili R, Kukreja RC (2012) Rapamycin protects against myocardial ischemia-reperfusion injury through JAK2-STAT3 signaling pathway. J Mol Cell Cardiol 53(6):858–869. https://doi.org/10.1016/j.yjmcc.2012.09.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Fineschi V (2015) Measuring myocyte oxidative stress and targeting cytokines to evaluate inflammatory response and cardiac repair after myocardial infarction. Curr Vasc Pharmacol 13(1):3–5

    Article  CAS  PubMed  Google Scholar 

  6. Gu Q, Kong Y, Yu ZB, Bai L, Xiao YB (2011) Hypoxia-induced SOCS3 is limiting STAT3 phosphorylation and NF-kappa B activation in congenital heart disease. Biochimie 93(5):909–920. https://doi.org/10.1016/j.biochi.2011.02.009

    Article  CAS  Google Scholar 

  7. Ha M, Kim VN (2014) Regulation of microRNA biogenesis. Nat Rev Mol Cell Biol 15(8):509–524. https://doi.org/10.1038/nrm3838

    Article  CAS  Google Scholar 

  8. Haghikia A, Missol-Kolka E, Tsikas D, Venturini L, Brundiers S, Castoldi M, Muckenthaler MU, Eder M, Stapel B, Thum T, Haghikia A, Petrasch-Parwez E, Drexler H, Hilfiker-Kleiner D, Scherr M (2011) Signal transducer and activator of transcription 3-mediated regulation of miR-199a-5p links cardiomyocyte and endothelial cell function in the heart: a key role for ubiquitin-conjugating enzymes. Eur Heart J 32:1287–1297. https://doi.org/10.1093/eurheartj/ehq369

    Article  CAS  PubMed  Google Scholar 

  9. Han Q, Yeung SC, Ip MS, Mak JC (2014) Cellular mechanisms in intermittent hypoxia-induced cardiac damage in vivo. J Physiol Biochem 70(1):201–213. https://doi.org/10.1007/s13105-013-0294-z

    Article  CAS  PubMed  Google Scholar 

  10. Hasnain SZ, Lourie R, Das I, Chen ACH, McGuckin MA (2012) The interplay between endoplasmic reticulum stress and inflammation. Immunol Cell Biol 90(3):260–270. https://doi.org/10.1038/icb.2011.112

    Article  CAS  PubMed  Google Scholar 

  11. Hassan T, Carroll TP, Buckley PG, Cummins R, O'Neill SJ, McElvaney NG, Greene CM (2014) miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and alpha1-antitrypsin deficiency. Am J Respir Crit Care Med 189(3):263–273. https://doi.org/10.1164/rccm.201306-1151OC

    Article  CAS  PubMed  Google Scholar 

  12. He S, Liu S, Wu X, Xin M, Ding S, Xin D, Ouyang H, Zhang J (2016) Protective role of downregulated MLK3 in myocardial adaptation to chronic hypoxia. J Physiol Biochem 73(3):371–380. https://doi.org/10.1007/s13105-017-0561-5

    Article  CAS  PubMed  Google Scholar 

  13. Heather LC, Cole MA, Tan JJ, Ambrose LJ, Pope S, Abd-Jamil AH, Carter EE, Dodd MS, Yeoh KK, Schofield CJ, Clarke K (2012) Metabolic adaptation to chronic hypoxia in cardiac mitochondria. Basic Res Cardiol 107(3):268. https://doi.org/10.1007/s00395-012-0268-2

    Article  CAS  PubMed  Google Scholar 

  14. Hohensinner PJ, Niessner A, Huber K, Weyand CM, Wojta J (2011) Inflammation and cardiac outcome. Curr Opin Infect Dis 24(3):259–264. https://doi.org/10.1097/QCO.0b013e328344f50f

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Hsu CY, Hsieh TH, Tsai CF, Tsai HP, Chen HS, Chang Y, Chuang HY, Lee JN, Hsu YL, Tsai EM (2014) miRNA-199a-5p regulates VEGFA in endometrial mesenchymal stem cells and contributes to the pathogenesis of endometriosis. J Pathol 232(3):330–343. https://doi.org/10.1002/path.4295

    Article  CAS  PubMed  Google Scholar 

  16. Jacoby JJ, Kalinowski A, Liu MG, Zhang SS, Gao Q, Chai GX, Ji L, Iwamoto Y, Li E, Schneider M, Russell KS, Fu XY (2003) Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc Natl Acad Sci U S A 100(22):12929–12934. https://doi.org/10.1073/pnas.2134694100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Jia YH, Zhou FH, Deng P, Fan Q, Li CH, Liu YW, Fu XQ, Zhou YC, Xu X, Sun XG (2012) Interleukin 6 protects H2O2-induced cardiomyocytes injury through upregulation of prohibitin via STAT3 phosphorylation. Cell Biochem Funct 30(5):426–431. https://doi.org/10.1002/cbf.2820

    Article  CAS  PubMed  Google Scholar 

  18. Lee C, Huang CH (2013) LASAGNA-Search: an integrated web tool for transcription factor binding site search and visualization. Biotechniques 54(3):141–153. https://doi.org/10.2144/000113999

    Article  CAS  PubMed  Google Scholar 

  19. Lee YB, Bantounas I, Lee DY, Phylactou L, Caldwell MA, Uney JB (2009) Twist-1 regulates the miR-199a/214 cluster during development. Nucleic Acids Res 37(1):123–128. https://doi.org/10.1093/nar/gkn920

    Article  CAS  PubMed  Google Scholar 

  20. Mathelier A, Fornes O, Arenillas DJ, Chen CY, Denay G, Lee J, Shi WQ, Shyr C, Tan G, Worsley-Hunt R, Zhang AW, Parcy F, Lenhard B, Sandelin A, Wasserman WW (2016) JASPAR 2016: a major expansion and update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 44(D1):D110–D115. https://doi.org/10.1093/nar/gkv1176

    Article  CAS  PubMed  Google Scholar 

  21. Neri M, Fineschi V, Di Paolo M, Pomara C, Riezzo I, Turillazzi E, Cerretani D (2015) Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. Curr Vasc Pharmacol 13(1):26–36

    Article  CAS  Google Scholar 

  22. Obana M, Maeda M, Takeda K, Hayama A, Mohri T, Yamashita T, Nakaoka Y, Komuro I, Takeda K, Matsumiya G, Azuma J, Fujio Y (2010) Therapeutic activation of signal transducer and activator of transcription 3 by interleukin-11 ameliorates cardiac fibrosis after myocardial infarction. Circulation 121(5):684–691. https://doi.org/10.1161/CIRCULATIONAHA.109.893677

    Article  CAS  PubMed  Google Scholar 

  23. Obana M, Miyamoto K, Murasawa S, Iwakura T, Hayama A, Yamashita T, Shiragaki M, Kumagai S, Miyawaki A, Takewaki K, Matsumiya G, Maeda M, Yoshiyama M, Nakayama H, Fujio Y (2012) Therapeutic administration of IL-11 exhibits the postconditioning effects against ischemia-reperfusion injury via STAT3 in the heart. Am J Phys Heart Circ Phys 303(5):H569–H577. https://doi.org/10.1152/ajpheart.00060.2012

    Article  CAS  Google Scholar 

  24. Rane S, He M, Sayed D, Vashistha H, Malhotra A, Sadoshima J, Vatner DE, Vatner SF, Abdellatif M (2009) Downregulation of miR-199a derepresses hypoxia-inducible factor-1alpha and Sirtuin 1 and recapitulates hypoxia preconditioning in cardiac myocytes. Circ Res 104(7):879–886. https://doi.org/10.1161/CIRCRESAHA.108.193102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sun XX, Zhang J, Hou ZH, Han QJ, Zhang C, Tian ZG (2015) miR-146a is directly regulated by STAT3 in human hepatocellular carcinoma cells and involved in anti-tumor immune suppression. Cell Cycle 14(2):243–252. https://doi.org/10.4161/15384101.2014.977112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Thuerauf DJ, Marcinko M, Gude N, Rubio M, Sussman MA, Glembotski CC (2006) Activation of the unfolded protein response in infarcted mouse heart and hypoxic cultured cardiac myocytes. Circ Res 99(3):275–282. https://doi.org/10.1161/01.RES.0000233317.70421.03

    Article  CAS  PubMed  Google Scholar 

  27. van Rooij E, Olson EN (2012) MicroRNA therapeutics for cardiovascular disease: opportunities and obstacles. Nat Rev Drug Discov 11(11):860–872. https://doi.org/10.1038/nrd3864

    Article  CAS  PubMed  Google Scholar 

  28. Wang M, Meng XB, Yu YL, Sun GB, Xu XD, Zhang XP, Dong X, Ye JX, Xu HB, Sun YF, Sun XB (2014) Elatoside C protects against hypoxia/reoxygenation-induced apoptosis in H9c2 cardiomyocytes through the reduction of endoplasmic reticulum stress partially depending on STAT3 activation. Apoptosis 19(12):1727–1735. https://doi.org/10.1007/s10495-014-1039-3

    Article  CAS  PubMed  Google Scholar 

  29. Zhang K, Kaufman RJ (2008) From endoplasmic-reticulum stress to the inflammatory response. Nature 454(7203):455–462. https://doi.org/10.1038/nature07203

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhou Y, Jia WK, Jian Z, Zhao L, Liu CC, Wang Y, Xiao YB (2017) Downregulation of microRNA199a5p protects cardiomyocytes in cyanotic congenital heart disease by attenuating endoplasmic reticulum stress. Mol Med Rep 16(3):2992–3000. https://doi.org/10.3892/mmr.2017.6934

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by research grants from the National Natural Science Foundation of China (Nos. 81571842 and 81270228).

Author information

Author notes

  1. Yang Zhou and Bo Pang contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiothoracic Surgery, The People’s Hospital of Leshan, No.222, Baita Street, Shizhong District, Leshan, 614000, Sichuan, People’s Republic of China

    Yang Zhou, Fan Zhang, Wei Liu & Huali Peng

  2. Department of Anesthesiology, The People’s Hospital of Leshan, 614000, Leshan, Sichuan, People’s Republic of China

    Bo Pang & Bin He

  3. Department of Cardiovascular Surgery, Xinqiao Hospital, The Third Military Medical University, Chongqing, 400037, People’s Republic of China

    Yingbin Xiao

  4. Department of High Altitude Hygiene, College of High Altitude Military Medicine, Third Military Medical University, No. 30 Gao Tan Yan Zheng Street, Sha Ping Ba District, Chongqing, 400038, People’s Republic of China

    Simin Zhou & Peng Li

Authors
  1. Yang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bo Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yingbin Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Simin Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bin He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Fan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Wei Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huali Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Peng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huali Peng or Peng Li.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, Y., Pang, B., Xiao, Y. et al. The protective microRNA-199a-5p-mediated unfolded protein response in hypoxic cardiomyocytes is regulated by STAT3 pathway. J Physiol Biochem 75, 73–81 (2019). https://doi.org/10.1007/s13105-018-0657-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-018-0657-6

Keywords

Search

Navigation