Skip to main content

Advertisement

SpringerLink
Log in

Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction

  • Original Contribution
  • Published:
Basic Research in Cardiology Aims and scope Submit manuscript

Abstract

Propylthiouracil (PTU), independent of its antithyroid effect, is recently found to have an antiatherosclerotic effect. The aim of this study is to determine the impact of PTU on phenotypic modulation of vascular smooth muscle cells (VSMCs), as phenotypic modulation may contribute to the growth of atherosclerotic lesions and neointimal formation after arterial injury. Propylthiouracil reduced neointimal formation in balloon-injured rat carotid arteries. In vitro, PTU may convert VSMCs from a serum-induced dedifferentiation state to a differentiated state, as indicated by a spindle-shaped morphology and an increase in the expression of SMC differentiation marker contractile proteins, including calponin and smooth muscle (SM)-myosin heavy chain (SM-MHC). Transient transfection studies in VSMCs demonstrated that PTU induced the activity of SMC marker genes (calponin and SM-MHC) promoters, indicating that PTU up-regulates these genes expression predominantly at the transcriptional level. Furthermore, PTU enhanced the expression of PTEN and inhibition of PTEN by siRNA knockdown blocked PTU-induced activation of contractile proteins expression and promoter activity. In the rat carotid injury model, PTU reversed the down-regulation of contractile proteins and up-regulated PTEN in the neointima induced by balloon injury. Propylthiouracil promotes VSMC differentiation, at lest in part, via induction of the PTEN-mediated pathway. These findings suggest a possible mechanism by which PTU may contribute to its beneficial effects on atherogenesis and neointimal formation after arterial 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

Similar content being viewed by others

References

  1. Chen WJ, Lin KH, Lai YJ, Yang SH, Pang JHS (2004) Protective effect of propylthiouracil independent of its hypothyroid effect on atherogenesis in cholesterol-fed rabbits: PTEN induction and inhibition of vascular smooth muscle cell proliferation and migration. Circulation 110:1313–1319

    Article  CAS  PubMed  Google Scholar 

  2. Chen WJ, Pang JHS, Lin KH, Yang SH (2009) Propylthiouracil, independent of its antithyroid effect, decreases VSMC collagen expression. Basic Res Cardiol 104:60–68

    Article  CAS  PubMed  Google Scholar 

  3. Christen T, Bochaton-Piallat ML, Neuville P, Rensen S, Redard M, Eys G, Gabbiani G (1999) Cultured porcine coronary artery smooth muscle cells: a new model with advanced differentiation. Cir Res 85:99–107

    CAS  Google Scholar 

  4. Dandre F, Owens GK (2004) Platelet-derived growth factor-BB and Ets-1 transcription factor negatively regulate transcription of multiple smooth muscle cell differentiation marker genes. Am J Physiol 286:H2042–H2051

    CAS  Google Scholar 

  5. Di Cristofano A, Pandolfi PP (2000) The multiple roles of PTEN in tumor suppression. Cell 100:387–390

    Article  CAS  PubMed  Google Scholar 

  6. Dwivedi A, Sala-Newby GB, George SJ (2008) Regulation of cell-matrix contacts and beta-catenin signaling in VSMC by integrin-linked kinase: implications for intimal thickening. Basic Res Cardiol 103:244–256

    Article  CAS  PubMed  Google Scholar 

  7. Garl PJ, Wenzlau JM, Walker HA, Whitelock JM, Costell M, Weiser-Evans MCM (2004) Perlecan-induced suppression of smooth muscle cell proliferation is mediated through increased activity of the tumor suppressor PTEN. Cir Res 94:175–183

    Article  CAS  Google Scholar 

  8. Han M, Wen JK, Zheng B, Cheng Y, Zhang C (2006) Serum deprivation results in redifferentiation of human umbilical vascular smooth muscle cells. Am J Physiol Cell Physiol 291:C50–C58

    Article  CAS  PubMed  Google Scholar 

  9. Huang J, Kontos CD (2002) Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Arterioscler Thromb Vasc Biol 22:745–751

    Article  CAS  PubMed  Google Scholar 

  10. Huang J, Niu XL, Pippen AM, Annex BH, Kontos CD (2005) Adenovirus-mediated intraarterial delivery of PTEN inhibits neointimal hyperplasia. Arterioscler Thromb Vasc Biol 25:354–358

    Article  CAS  PubMed  Google Scholar 

  11. Huang YH, Lee CY, Tai PJ, Yen CC, Liao CY, Chen WJ, Liao CJ, Cheng WL, Chen RN, Wu SM, Wang CS, Lin KH (2006) Indirect regulation of human dehydroepiandrosterone sulfotransferase family 1A member 2 by thyroid hormones. Endocrinology 147:2481–2489

    Article  CAS  PubMed  Google Scholar 

  12. Ji R, Cheng Y, Yue J, Yang J, Liu X, Chen H, Dean DB, Zhang C (2007) Micro RNA expression signature and antisense-mediated depletion reveal an essential role of microRNA in vascular neointimal lesion formation. Cir Res 100:1579–1588

    Article  CAS  Google Scholar 

  13. Li S, Sims S, Jiao Y, Chow LH, Pickering JG (1999) Evidence from a novel human cell clone that adult vascular smooth muscle cells can convert reversibly between noncontractile and contractile phenotypes. Cir Res 85:338–348

    CAS  Google Scholar 

  14. Martin KA, Rzucidlo EM, Merenick BL, Fingar DC, Brown DJ, Wagner RJ, Powell RJ (2004) The mTOR/p70 S6K1 pathway regulates vascular smooth muscle cell differentiation. Am J Physiol Cell Physiol 286:C507–C517

    Article  CAS  PubMed  Google Scholar 

  15. Mechanick JI, Davies TF (1997) Medical management of hyperthyroidism: theoretical and practical aspects. In: Falk SA (ed) Thyroid disease, 2nd edn. Lippincott-Raven Publishers, Philadelphia, pp 253–296

    Google Scholar 

  16. Morice MC, Serruys PW, Sousa JF, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guabliumi G, Molnar F, Falotico R (2002) A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 346:1773–1780

    Article  CAS  PubMed  Google Scholar 

  17. Mourani PM, Garl PJ, Wenzlau JM, Carpenter TC, Stenmark KR, Weiser-Evans MCM (2004) Unique, highly proliferative growth phenotype expressed by embryonic and neointimal smooth muscle cells is driven by constitutive Akt, mTOR, and p70S6K signaling and is actively repressed by PTEN. Circulation 109:1299–1306

    Article  CAS  PubMed  Google Scholar 

  18. Nemenoff RA, Simpson PA, Furgeson SB, Kaplan-Albuquerque N, Crossno J, Garl PJ, Cooper J, Weiser-Evans MCM (2008) Targeted deletion of PTEN in smooth muscle cells results in vascular remodeling and recruitment of progenitor cells through induction of stromal cell-derived factor-1α. Cir Res 102:1036–1045

    Article  CAS  Google Scholar 

  19. Nilsson AH, Lovdahl C, Blomgren K, Kallin B, Thyberg J (1997) Expression of phenotype- and proliferation-related genes in rat aortic smooth muscle cells in primary culture. Cardiovasc Res 34:418–430

    Article  Google Scholar 

  20. Owens GK (2004) Molecular regulation of vascular smooth muscle cell differentiation in development and disease. Physiol Rev 84:767–801

    Article  CAS  PubMed  Google Scholar 

  21. Regan CP, Adam PJ, Madsen CS, Owens GK (2000) Molecular mechanisms of decreased smooth muscle differentiation marker expression after balloon injury. J Clin Invest 106:1139–1147

    Article  CAS  PubMed  Google Scholar 

  22. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  23. Siddall HK, Warrell CE, Yellon DM, Mocanu MM (2008) Ischemia-reperfusion injury and cardioprotection: investigating PTEN, the phosphatase that negatively regulates PI3K, using a congenital model of PTEN haploinsufficiency. Basic Res Cardiol 103(6):560–568

    Article  CAS  PubMed  Google Scholar 

  24. Worth NF, Rolfe BE, Song J, Campbell GR (2001) Vascular smooth muscle cell phenotypic modulation in culture is associated with reorganization of contractile and cytoskeletal proteins. Cell Motil Cytoskeleton 49:130–145

    Article  CAS  PubMed  Google Scholar 

  25. Zhang C (2008) The role of inflammatory cytokines in endothelial dysfunction. Basic Res Cardiol 103:398–406

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Chang Gung Research Grant Foundation [G32102, and G331023] and National Science Council Grant [NSC-94-2314-B-182A-198]. We thank Mr. Chih-Chun Chen for his technical assistance in confocal microscope.

Author information

Authors and Affiliations

  1. First Cardiovascular Division, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Fu-Shin Road no 5, Kwei-Shan, Tao-Yuan, 333, Taiwan

    Wei-Jan Chen, Dany-Young Lee, Lung-An Hsu & Chi-Tai Kuo

  2. Graduate Institute of Clinical Medical Sciences, Tao-Yuan, Taiwan

    Jong-Hwei S. Pang

  3. Department of Biochemistry, Chang Gung University, Tao-Yuan, Taiwan

    Kwang-Huei Lin

Authors
  1. Wei-Jan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jong-Hwei S. Pang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kwang-Huei Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Dany-Young Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lung-An Hsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Chi-Tai Kuo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wei-Jan Chen.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 11 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, WJ., Pang, JH.S., Lin, KH. et al. Propylthiouracil, independent of its antithyroid effect, promotes vascular smooth muscle cells differentiation via PTEN induction. Basic Res Cardiol 105, 19–28 (2010). https://doi.org/10.1007/s00395-009-0045-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00395-009-0045-z

Keywords

Search

Navigation