Skip to main content

Advertisement

SpringerLink
Log in

AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation

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

Abstract

Increased evidence indicates that adenosine monophosphate-activated protein kinase (AMPK) plays a vital role in vascular homeostasis, especially under hypoxia, and protects against the progression of pulmonary hypertension (PH). However, the role of AMPK in the pathogenesis of PH remains to be clarified. In the present study, we confirmed that a loss of AMPKα2 exacerbated the development of PH by using hypoxia-induced PH model in AMPKα2 −/− mice. After a 4-week period of hypoxic exposure, AMPKα2 −/− mice exhibited more severe pulmonary vascular remodeling and pulmonary vascular smooth muscle cell (SMC) proliferation when compared with wild type (WT) mice. In vitro, AMPKα2 knockdown promoted the proliferation of pulmonary arterial smooth muscle cells (PASMCs) under hypoxia. This phenomenon was accompanied by upregulated Skp2 and downregulated p27kip1 expression and was abolished by rapamycin, an inhibitor of mTOR. These results indicate that AMPKα2 deficiency exacerbates hypoxia-induced PH by promoting PASMC proliferation via the mTOR/Skp2/p27kip1 signaling axis. Therefore, enhanced AMPKα2 activity might underlie a novel therapeutic strategy for the management of PH.

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

Similar content being viewed by others

References

  1. Auld CA, Fernandes KM, Morrison RF (2007) Skp2-mediated p27(Kip1) degradation during S/G2 phase progression of adipocyte hyperplasia. J Cell Physiol 211:101–111. https://doi.org/10.1002/jcp.20915

    Article  CAS  PubMed  Google Scholar 

  2. Bond M, Wu YJ (2011) Proliferation unleashed: the role of Skp2 in vascular smooth muscle cell proliferation. Front Biosci (Landmark edition) 16:1517–1535

    Article  CAS  Google Scholar 

  3. Cetrullo S, D’Adamo S, Tantini B, Borzi RM, Flamigni F (2015) mTOR, AMPK, and Sirt1: key players in metabolic stress management. Crit Rev Eukaryot Gene Expr 25:59–75

    Article  Google Scholar 

  4. Chen H, Mo X, Yu J, Huang S, Huang Z, Gao L (2014) Interference of Skp2 effectively inhibits the development and metastasis of colon carcinoma. Mol Med Rep 10:1129–1135. https://doi.org/10.3892/mmr.2014.2308

    Article  CAS  PubMed  Google Scholar 

  5. Conradie R, Bruggeman FJ, Ciliberto A, Csikasz-Nagy A, Novak B, Westerhoff HV, Snoep JL (2010) Restriction point control of the mammalian cell cycle via the cyclin E/Cdk2:p27 complex. FEBS J 277:357–367. https://doi.org/10.1111/j.1742-4658.2009.07473.x

    Article  CAS  PubMed  Google Scholar 

  6. Council NR (2011) Guide for the care and use of laboratory animals. In: 8th (ed) Guide for the care and use of laboratory animals. National Academies Press, Washington (DC). https://doi.org/10.17226/12910

  7. Dazert E, Hall MN (2011) mTOR signaling in disease. Curr Opin Cell Biol 23:744–755. https://doi.org/10.1016/j.ceb.2011.09.003

    Article  CAS  PubMed  Google Scholar 

  8. Fisslthaler B, Fleming I (2009) Activation and signaling by the AMP-activated protein kinase in endothelial cells. Circ Res 105:114–127. https://doi.org/10.1161/CIRCRESAHA.109.201590

    Article  CAS  PubMed  Google Scholar 

  9. Fujita T, Liu W, Doihara H, Wan Y (2008) Regulation of Skp2-p27 axis by the Cdh1/anaphase-promoting complex pathway in colorectal tumorigenesis. Am J Pathol 173:217–228. https://doi.org/10.2353/ajpath.2008.070957

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hardie DG (2011) AMP-activated protein kinase: an energy sensor that regulates all aspects of cell function. Genes Dev 25:1895–1908. https://doi.org/10.1101/gad.17420111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ibe JC, Zhou Q, Chen T, Tang H, Yuan JX, Raj JU, Zhou G (2013) Adenosine monophosphate-activated protein kinase is required for pulmonary artery smooth muscle cell survival and the development of hypoxic pulmonary hypertension. Am J Respir Cell Mol Biol 49:609–618. https://doi.org/10.1165/rcmb.2012-0446OC

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Inoki K, Ouyang H, Zhu T, Lindvall C, Wang Y, Zhang X, Yang Q, Bennett C, Harada Y, Stankunas K, Wang CY, He X, MacDougald OA, You M, Williams BO, Guan KL (2006) TSC2 integrates Wnt and energy signals via a coordinated phosphorylation by AMPK and GSK3 to regulate cell growth. Cell 126:955–968. https://doi.org/10.1016/j.cell.2006.06.055

    Article  CAS  PubMed  Google Scholar 

  13. Jiang W, Zhu Z, Thompson HJ (2008) Dietary energy restriction modulates the activity of AMP-activated protein kinase, Akt, and mammalian target of rapamycin in mammary carcinomas, mammary gland, and liver. Cancer Res 68:5492–5499. https://doi.org/10.1158/0008-5472.can-07-6721

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ke R, Liu L, Zhu Y, Li S, Xie X, Li F, Song Y, Yang L, Gao L, Li M (2016) Knockdown of AMPKalpha2 promotes pulmonary arterial smooth muscle cells proliferation via mTOR/Skp2/p27(Kip1) signaling pathway. Int J Mol Sci 17. https://doi.org/10.3390/ijms17060844

  15. Kopsiaftis S, Sullivan KL, Garg I, Taylor JA 3rd, Claffey KP (2016) AMPKalpha2 regulates bladder cancer growth through SKP2-mediated degradation of p27. Mol Cancer Res 14:1182–1194. https://doi.org/10.1158/1541-7786.mcr-16-0111

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lai YC, Potoka KC, Champion HC, Mora AL, Gladwin MT (2014) Pulmonary arterial hypertension: the clinical syndrome. Circ Res 115:115–130. https://doi.org/10.1161/CIRCRESAHA.115.301146

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lai YC, Tabima DM, Dube JJ, Hughan KS, Vanderpool RR, Goncharov DA, St Croix CM, Garcia-Ocana A, Goncharova EA, Tofovic SP, Mora AL, Gladwin MT (2016) SIRT3-AMP-activated protein kinase activation by nitrite and metformin improves hyperglycemia and normalizes pulmonary hypertension associated with heart failure with preserved ejection fraction. Circulation 133:717–731. https://doi.org/10.1161/circulationaha.115.018935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Larrea MD, Wander SA, Slingerland JM (2009) p27 as Jekyll and Hyde: regulation of cell cycle and cell motility. Cell Cycl (Georgetown, Tex) 8:3455–3461. https://doi.org/10.4161/cc.8.21.9789

    Article  CAS  Google Scholar 

  19. McLaughlin VV, Shah SJ, Souza R, Humbert M (2015) Management of pulmonary arterial hypertension. J Am Coll Cardiol 65:1976–1997. https://doi.org/10.1016/j.jacc.2015.03.540

    Article  PubMed  Google Scholar 

  20. Ogawa A, Firth AL, Yao W, Madani MM, Kerr KM, Auger WR, Jamieson SW, Thistlethwaite PA, Yuan JX (2009) Inhibition of mTOR attenuates store-operated Ca2+ entry in cells from endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 297:L666–L676. https://doi.org/10.1152/ajplung.90548.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Omura J, Satoh K, Kikuchi N, Satoh T, Kurosawa R, Nogi M, Otsuki T, Kozu K, Numano K, Suzuki K, Sunamura S, Tatebe S, Aoki T, Sugimura K, Miyata S, Hoshikawa Y, Okada Y, Shimokawa H (2016) Protective roles of endothelial AMP-activated protein kinase against hypoxia-induced pulmonary hypertension in mice. Circ Res 119:197–209. https://doi.org/10.1161/circresaha.115.308178

    Article  CAS  PubMed  Google Scholar 

  22. Pacher P, Nagayama T, Mukhopadhyay P, Batkai S, Kass DA (2008) Measurement of cardiac function using pressure-volume conductance catheter technique in mice and rats. Nat Protoc 3:1422–1434. https://doi.org/10.1038/nprot.2008.138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ray A, James MK, Larochelle S, Fisher RP, Blain SW (2009) p27Kip1 inhibits cyclin D-cyclin-dependent kinase 4 by two independent modes. Mol Cell Biol 29:986–999. https://doi.org/10.1128/mcb.00898-08

    Article  CAS  PubMed  Google Scholar 

  24. Salt IP, Hardie DG (2017) AMP-activated protein kinase: an ubiquitous signaling pathway with key roles in the cardiovascular system. Circ Res 120:1825–1841. https://doi.org/10.1161/CIRCRESAHA.117.309633

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Song P, Wang S, He C, Wang S, Liang B, Viollet B, Zou MH (2011) AMPKalpha2 deletion exacerbates neointima formation by upregulating Skp2 in vascular smooth muscle cells. Circ Res 109:1230–1239. https://doi.org/10.1161/circresaha.111.250423

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Song Y, Wu Y, Su X, Zhu Y, Liu L, Pan Y, Zhu B, Yang L, Gao L, Li M (2016) Activation of AMPK inhibits PDGF-induced pulmonary arterial smooth muscle cells proliferation and its potential mechanisms. Pharmacol Res 107:117–124. https://doi.org/10.1016/j.phrs.2016.03.010

    Article  CAS  PubMed  Google Scholar 

  27. Stacher E, Graham BB, Hunt JM, Gandjeva A, Groshong SD, McLaughlin VV, Jessup M, Grizzle WE, Aldred MA, Cool CD, Tuder RM (2012) Modern age pathology of pulmonary arterial hypertension. Am J Respir Crit Care Med 186:261–272. https://doi.org/10.1164/rccm.201201-0164OC

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sutendra G, Michelakis ED (2013) Pulmonary arterial hypertension: challenges in translational research and a vision for change. Sci Transl Med 5:208sr205. https://doi.org/10.1126/scitranslmed.3005428

    Article  Google Scholar 

  29. Tajsic T, Morrell NW (2011) Smooth muscle cell hypertrophy, proliferation, migration and apoptosis in pulmonary hypertension. Compr Physiol 1:295–317. https://doi.org/10.1002/cphy.c100026

    Article  PubMed  Google Scholar 

  30. Totary-Jain H, Sanoudou D, Dautriche CN, Schneller H, Zambrana L, Marks AR (2012) Rapamycin resistance is linked to defective regulation of Skp2. Cancer Res 72:1836–1843. https://doi.org/10.1158/0008-5472.can-11-2195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Vila IK, Yao Y, Kim G, Xia W, Kim H, Kim SJ, Park MK, Hwang JP, Gonzalez-Billalabeitia E, Hung MC, Song SJ, Song MS (2017) A UBE2O-AMPKalpha2 axis that promotes tumor initiation and progression offers opportunities for therapy. Cancer Cell 31:208–224. https://doi.org/10.1016/j.ccell.2017.01.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zang Y, Yu LF, Nan FJ, Feng LY, Li J (2009) AMP-activated protein kinase is involved in neural stem cell growth suppression and cell cycle arrest by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside and glucose deprivation by down-regulating phospho-retinoblastoma protein and cyclin D. J Biol Chem 284:6175–6184. https://doi.org/10.1074/jbc.M806887200

    Article  CAS  PubMed  Google Scholar 

  33. Zhan JK, Wang YJ, Wang Y, Tang ZY, Tan P, Huang W, Liu YS (2014) Adiponectin attenuates the osteoblastic differentiation of vascular smooth muscle cells through the AMPK/mTOR pathway. Exp Cell Res 323:352–358. https://doi.org/10.1016/j.yexcr.2014.02.016

    Article  CAS  PubMed  Google Scholar 

  34. Zoncu R, Efeyan A, Sabatini DM (2011) mTOR: from growth signal integration to cancer, diabetes and ageing. Nat Rev Mol Cell Biol 12:21–35. https://doi.org/10.1038/nrm3025

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors thank the Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, and Institute of Respiratory Diseases, Xinqiao Hospital, Army Medical University, for their support for this study.

Funding

This study was funded by the National Natural Science Foundation of China (grant nos. 81370004 and 81270228).

Author information

Authors and Affiliations

  1. Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, People’s Republic of China

    Hai-Long Wang, Fu-Qin Tang, Yun-Han Jiang, Yu Zhu, Zhao Jian & Ying-Bin Xiao

Authors
  1. Hai-Long Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fu-Qin Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yun-Han Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yu Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhao Jian
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ying-Bin Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Zhao Jian or Ying-Bin Xiao.

Ethics declarations

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. This article does not contain any studies with human participants performed by any of the authors.

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

1. AMPKα2 knockout exacerbates hypoxia-induced pulmonary hypertension (PH) in mice.

2. AMPKα2 deficiency promotes PASMC proliferation under hypoxia condition.

3. mTOR activation mediates the effect of AMPKα2 on PASMC proliferation.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, HL., Tang, FQ., Jiang, YH. et al. AMPKα2 deficiency exacerbates hypoxia-induced pulmonary hypertension by promoting pulmonary arterial smooth muscle cell proliferation. J Physiol Biochem 76, 445–456 (2020). https://doi.org/10.1007/s13105-020-00742-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s13105-020-00742-4

Keywords

Search

Navigation