Skip to main content
SpringerLink
Log in

Sarpogrelate Inhibits Genes Involved in Vascular Neointimal Hyperplasia and Remodeling

  • Chapter
  • First Online:
Atherosclerosis, Hypertension and Diabetes

Part of the book series: Progress in Experimental Cardiology ((PREC,volume 8))

Abstract

Although basic molecular mechanisms of vascular neointimal hyperplasia leading to vascular remodeling remain unknown, it is generally held that various genes are upregu-lated or inhibited during this process. We have recently discovered that a specific serotonin receptor (5-HT2A) antagonist, sarpogrelate, inhibits vascular remodeling by suppressing the serotonin-induced c-fos and c-jun heterodimerization. By conducting RT-PCR and cell transfection studies, we have shown that over-expression of the 5-HT2A receptor enhanced while sarpogrelate inhibited vascular neoinitmal hyperplasia and remodeling by binding with the ligand binding domain (localized in the third intra-cytoplasmic loop) of the 5-HT2A receptor. These data are interpreted to suggest the therapeutic potential of sarpogrelate in cardiovascular diseases such as atherosclerosis, myocardial ischemia, and coronary artery restenosis.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Watts SW, Yeum CH, Campbell G, Webb RC. 1996. Serotonin stimulates protein tyrosyl phosphorylation and vascular contraction via tyrosine kinase. J Vasc Res 33:288–298.

    Article  PubMed  CAS  Google Scholar 

  2. Lee SL, Wang WW, Fanburg BL. 1996. Nitroprusside inhibits serotonin-induced mitogenesis and tyrosine phosphorylation of smooth muscle cells. Am J Physiol 270:L362–L367.

    PubMed  CAS  Google Scholar 

  3. Lee SL, Wang WW, Fanburg BL. 1998. Superoxide as an intermediate signal for serotonin-induced mitogenesis. Free Rad Biol Med 24:855–858.

    Article  PubMed  Google Scholar 

  4. Fanburg BL, Lee SL. 1997. A new role for an old molecule: serotonin as a mitogen. Am J Physiol 272:L795–806.

    PubMed  CAS  Google Scholar 

  5. Lee SL, Wang WW, Joseph PM, Hales CA, Fanburg BL. 1997. Inhibitory effect of heparin on serotonin-induced hyperplasia and hypertrophy of smooth muscle cells. Am J Respir Cell Mol Biol 17:78–83.

    PubMed  Google Scholar 

  6. Tamura K, Kanzaki T, Saito Y, Otabe M, Morisaki N. 1997. Serotonin (5-hydroxytryptamine, 5-HT) enhances migration of rat aortic smooth muscle cells through 5-HT2 receptors. Atherosclerosis 132:139–143.

    Article  PubMed  CAS  Google Scholar 

  7. Pakala R, Benedict CR. 1998. Effect of serotonin and thromboxane A2 on endothelial cell prolif-eration: effect of specific receptor antagonists. J Lab Clin Med 131:527–537.

    Article  PubMed  CAS  Google Scholar 

  8. Hoyer D, Harmon JP, Martin GR. 2002. Molecular, pharmacological and functional diversity of 5-HT receptors. Pharmacol Biochem Behav 71:533–554.

    Article  PubMed  CAS  Google Scholar 

  9. Ramage AG. 2001. Central cardiovascular regulation and 5-hydroxytryptamine receptors. Res Bull 56:425–439.

    Article  CAS  Google Scholar 

  10. Assender JW, Irenius E, Fredholm BB. 1997. 5-Hydroxytryptamine, angiotensin and bradykinin transiently increase intracellular calcium concentrations and PKC-alpha activity, but do not induce mitogenesis in human vascular smooth muscle cells. Acta Physiol Scand 160:207–217.

    Article  PubMed  CAS  Google Scholar 

  11. Sharma SK, Zahradka P, Chapman D, Kumamoto H, Takeda N, Dhalla NS. 1999. Inhibition of serotonin-induced vascular smooth muscle cell proliferation by sarpogrelate. J Pharmacol Exp Therapeut 290:1475–1481.

    CAS  Google Scholar 

  12. Sharma SK, Del Rizzo DF, Zahradka P, Bhangu SK, Werner JP, Kumamoto H, Takeda N, Dhaila NS. 2001. Sarpogrelate inhibits serotonin-induced proliferation of porcine coronary artery smooth muscle cells: Implications for long term graft potency. Ann Thorac Surg 71:1856–1865.

    Article  PubMed  CAS  Google Scholar 

  13. Mawatari K, Komori K, Kuma S, Yamamura S, Ishii T, Sugimachi K. 1997. Effects of serotonin and endothelin on the smooth muscle cells of autogenous vein grafts. Br J Surg 84:1419–1424.

    Article  PubMed  CAS  Google Scholar 

  14. Kuga T, Kadokami T, Kuwata K, Hata H, Ohara Y, Egashira K, Shimokawa H, Takeshita A. 1997. Central role of vascular smooth muscle hyperreactivity in coronary hyperconstriction after balloon injury in miniature pigs. Coron Artery Dis 8:69–75.

    Article  PubMed  CAS  Google Scholar 

  15. Chan PD, Findlay JM, Vollrath B, Cook DA, Grace M, Chen MH, Ashforth RA. 1995. Pharmacological and morphological effects of in-vitro transluminal balloon angioplasty on normal and vasospastic canine basilar arteries. J Neurosurg 83:522–530.

    Article  PubMed  CAS  Google Scholar 

  16. Semenchuk LA, Di Salvo J. 1995. Receptor-activated increases in intracellular calcium and protein tyrosine phosphorylation in vascular smooth muscle cells. FEBS Lett 370:127–130.

    Article  PubMed  CAS  Google Scholar 

  17. Kahn AM, Allen JC, Seidel CL, Song T. 1994. Insulin inhibits serotonin-induced Ca2+ influx in vascular smooth muscle. Circulation 90:384–390.

    Article  PubMed  CAS  Google Scholar 

  18. Kitagawa S, Yamaguchi Y, Kunitomo M, Imaizumi N, Fujiwara M. 1993. Altered vasoconstrictor responsiveness in vitamin D-induced arteriosclerotic rat aortas. Jpn J Pharmacol 61:283–289.

    Article  PubMed  CAS  Google Scholar 

  19. Florian JA, Watts SW 1998. Integration of mitogen-activated protein kinase kinase activation in vascular 5-hydroxytryptamine2A receptor signal transduction. J Pharmacol Exp Ther 284:346–355.

    PubMed  CAS  Google Scholar 

  20. Guillet-Deniau I, Burnol AF, Girard J. 1997. Identification and localization of a skeletal muscle secrotonin 5-HT2A receptor coupled to the Jak/STAT pathway. J Biol Chem 272:14825–14829.

    Article  PubMed  CAS  Google Scholar 

  21. Hara H, Oskabe M, Kitajima A, Tamao Y, Kikumoto R. 1991. MCI-9042, a new antiplatelet agent is a selective S2-serotonergic receptor antagonist. Thromb Haemost 65:415–420.

    PubMed  CAS  Google Scholar 

  22. Hara H, Kitajima A, Shimada H, Tamao Y. 1994. Antithrombotic effect of MCI-9042, a new antiplatelet agent on experimental thrombosis models. Thromb Haemost 66:484–488.

    Google Scholar 

  23. Kanamori A, Matoba K, Yajima Y. 1994. Effects of sarpogrelate on serotonin-induced increase in cytosolic Ca2+in cultured rat mesangial cells. Life Sci 55:PL 365–370.

    Article  Google Scholar 

  24. Hirafuji M, Nezu A, Kanai Y, Ebihara T, Kawahara F, Tanimura A, Minami M. 1998. Effect of 5-hydroxytryptamine on intracellular calcium dynamics in cultured rat vascular smooth muscle cells. Res Commun Mol Pathol Pharmacol 99:305–319.

    PubMed  CAS  Google Scholar 

  25. Lee SL, Wang WW, Fanburg BL. 1997. Association of Tyr phosphorylation of GTPase-activating protein with mitogenic action of serotonin. Am J Physiol 272:C223–C230.

    PubMed  CAS  Google Scholar 

  26. Di Salvo J, Raatz Nelson S. 1998. Stimulation of G-protein coupled receptors in vascular smooth muscle cells induces tyrosine kinase dependent increases in calcium without tyrosine phosphorylation of phospholipase C gamma-. FEBS Lett 422:85–88.

    Article  PubMed  Google Scholar 

  27. Watts SW, Baez M, Webb RC. 1996. The 5-hydroxytryptamine2B receptor and 5-HT receptor signal transduction in mesenteric arteries from deoxycorticosterone acetate-salt hypertensive rats. J Pharmacol Exp Ther 277:1103–1113.

    PubMed  CAS  Google Scholar 

  28. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. 1994. Serotonin produces both hyperplasia and hypertrophy of bovine pulmonary artery smooth muscle cells in culture. Am J Physiol 266:L46–L52.

    PubMed  CAS  Google Scholar 

  29. Lee SL, Wang WW, Moore BJ, Fanburg BL. 1991. Dual effect of serotonin on growth of bovine pulmonary artery smooth muscle cells in culture. Circ Res 68:1362–1368.

    Article  PubMed  CAS  Google Scholar 

  30. Verma IM, Ransone LJ, Visvader J, Sassone-Corsi P, Lamph WW 1990. fos-jun conspiracy: implications for the cell. Ciba Found Symp 150:128–137.

    PubMed  CAS  Google Scholar 

  31. McKnight SL. 1991. Molecular Zippers in Gene Regulation. Sci American 264:54–64.

    Article  CAS  Google Scholar 

  32. Ng KW, Ridgway P, Cohen DR, Tremethick DJ. 1997. The binding of a Fos/Jun heterodimer can completely disrupt the structure of a nucleosome. EMBO J 16:2072–2085.

    Article  PubMed  CAS  Google Scholar 

  33. Kerppola TK, Curran T. 1997. The transcription activation domains of Fos and Jun induce DNA bending through electrostatic interactions. EMBO J 16:2907–2916.

    Article  PubMed  CAS  Google Scholar 

  34. Leonard DA, Rajaram N, Kerppola TK. 1997. Structural basis of DNA bending and oriented heterodimer binding by the basic leucine zipper domains of Fos and Jun. Proc Natl Acad Sci (USA) 94:4913–4918.

    Article  CAS  Google Scholar 

  35. McGill G, Fisher DE. 1998. DNA bending and the curious case of Fos/Jun. Chem Biol 5.R29–R38.

    Article  PubMed  CAS  Google Scholar 

  36. Sitlani A, Crothers DM. 1998. DNA-binding domains of Fos and Jun do not induce DNA curvature: an investigation with solution and gel methods. Proc Natl Acad Sci (USA) 95:1404–1409.

    Article  CAS  Google Scholar 

  37. Chen L, Glover JN, Hogan PG, Rao A, Harrison SC. 1996. Structure of the DNA-binding domains from NFAT, Fos and jun bound specifically to DNA. Nature 392:42–48.

    Article  Google Scholar 

  38. Lee SL, Wang WW, Lanzillo JJ, Fanburg BL. 1994. Regulation of serotonin-induced DNA synthesis of bovine pulmonary artery smooth muscle cells. Am J Physiol 266:L53–L60.

    PubMed  CAS  Google Scholar 

  39. Yang H, Lu D, Yu K, Raizada MK. 1996. Regulation of neuromodulatory actions of angiotensin II in the brain neurons by the Ras-dependent mitogen-activated protein kinase pathway. J Neurosci 16:4047–4058.

    PubMed  CAS  Google Scholar 

  40. Yang H, Lu D, Raizada MK. 1997. Angiotensin II-induced phosphorylation of the AT1 receptor from rat brain neurons. Hypertension 30:351–357.

    Article  PubMed  CAS  Google Scholar 

  41. Yang H, Lu D, Vinson GP, Raizada MK. 1997. Involvement of MAP kinase in angiotensin II-induced phosphorylation and intracellular targeting of neuronal AT1 receptors. J Neurosci 17:1660–1669.

    PubMed  CAS  Google Scholar 

  42. Watts SW, Cohen ML, Mooney PQ, Johnson BG, Schoepp DD, Baez M. 1994. Disruption of potential alpha-helix in the G loop of the guinea pig 5-hydroxytryptamine2 receptor does not prevent receptor coupling to phosphoinositide hydrolysis. J Neurochem 62:934–943.

    Article  PubMed  CAS  Google Scholar 

  43. Watts SW. 1996. Serotonin activates the mitogen-activated protein kinase pathway in vascular smooth muscle: use of the mitogen-activated protein kinase kinase inhibitor PD098059. J Pharmacol Exp Ther 279:1541–1550.

    PubMed  CAS  Google Scholar 

  44. Assender JW, Southgate KM, Hallett MB, Newby AC. 1992. Inhibition of proliferation, but not of Ca2+mobilization, by cyclic AMP and GMP in rabbit aortic smooth-muscle cells. Biochem J 288:527–532.

    PubMed  CAS  Google Scholar 

  45. Assender JW, Irenius E, Fredholm BB. 1996. Endothelin-1 causes a prolonged protein kinase C activation and acts as a co-mitogen in vascular smooth muscle cells. Acta Physiol Scand 157:451–460.

    Article  PubMed  CAS  Google Scholar 

  46. Lafont A, Libby P. 1998. The smooth muscle cell: Sinner or saint in restenosis and the acute coronary syndrome? J Am Coll Cardiol 32:283–285.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. University of North Dakota School of Medicine and Health Sciences, Department of Physiology, Pharmacology, and Therapeutics, Grand Forks, ND, U.S.A., Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, University of Manitoba, Departments of Physiology and Medicure, Winnipeg, Manitoba, Canada, and Aoto Hospital, Jikei University, Tokyo, Japan

    Nobuakira Takeda

Authors
  1. Sushil K. Sharma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nobuakira Takeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Amarjit S. Arneja
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Narnjan S. Dhalla
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Division of Stroke & Vascular Disease, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Grant N. Pierce PhD, FACC (Professor & Director) (Professor & Director)

  2. Department of Medicine, Jikei University School of Medicine, Tokyo, Japan

    Makoto Nagano MD, PhD (Professor Emeritus) (Professor Emeritus)

  3. Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Centre, Faculty of Medicine, University of Manitoba, Winnipeg, Canada

    Peter Zahradka PhD (Associate Professor) & Naranjan S. Dhalla PhD, MD (Hon), DSc (Hon) (Distinguished Professor and Director) (Associate Professor) &  (Distinguished Professor and Director)

Rights and permissions

Reprints and permissions

Copyright information

© 2003 Springer Science+Business Media New York

About this chapter

Cite this chapter

Sharma, S.K., Takeda, N., Arneja, A.S., Dhalla, N.S. (2003). Sarpogrelate Inhibits Genes Involved in Vascular Neointimal Hyperplasia and Remodeling. In: Pierce, G.N., Nagano, M., Zahradka, P., Dhalla, N.S. (eds) Atherosclerosis, Hypertension and Diabetes. Progress in Experimental Cardiology, vol 8. Springer, Boston, MA. https://doi.org/10.1007/978-1-4419-9232-1_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-9232-1_15

  • Published:

  • Publisher Name: Springer, Boston, MA

  • Print ISBN: 978-1-4613-4850-4

  • Online ISBN: 978-1-4419-9232-1

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation