Skip to main content
SpringerLink
Log in

Cellular and Molecular Mechanisms Associated with Salicylate Inhibition of Intimal Hyperplasia Following Balloon Catheter-Induced Vascular Injury

  • Chapter
  • First Online:
Molecular Defects in Cardiovascular Disease

  • 593 Accesses

Abstract

Angioplasty followed by stent placement, bare or drug-eluting, proved to be a major step forward in the treatment of coronary and carotid artery disease. It was soon recognized that patients undergoing these procedures presented with restenosis within 6 months. The cause of these failures was the development of intimal hyperplasia. Aspirin, acetylsalicylic acid, soon became a focus of therapeutic intervention alone or in combination with other drugs due to its antiplatelet properties. When it was recognized that inflammation is a primary underlying factor in vascular disease, the use of aspirin was further encouraged. More recently, the anti-inflammatory proprieties of aspirin other than inhibition of cyclooxygenase activity have been described, namely, alterations in the expression and formation of proinflammatory molecules such as NF-κB. However, aspirin has gastrointestinal side effects and bleeding problems. Salicylates became the drug of interest, and more recently salsalate, the dimeric form of salicylic acid, is being recognized for similar anti-inflammatory actions as well as for lowering hyperglycemic glucose levels in type 2 diabetics without the deleterious side effects of aspirin. As revascularization procedures in type 2 diabetics have proven to produce a greater degree of intimal hyperplasia and, therefore, procedure failures, the effect of salsalate on the development of intimal hyperplasia in animals exhibiting symptoms of the metabolic syndrome was studied; the authors reported salsalate decreased intimal hyperplasia, increased eNOS expression, decreased NF-κB and VEGF expression. It is concluded in this chapter that clinical trials are indicated to define the effect of salsalate on the development of intimal hyperplasia and inflammation.

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 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
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

References

  1. Hall D, Gruentzig A. Percutaneous transluminal coronary angioplasty: current procedure and future direction. AJR Am J Roentgenol. 1984;142:13–6.

    PubMed  CAS  Google Scholar 

  2. King SB. Percutaneous transluminal coronary angioplasty. J Am Coll Cardiol. 1999;34:615–7.

    Article  PubMed  Google Scholar 

  3. Gruberg L, Dangas G, Leon MB. Coronary artery stents: appropriate use of adjunctive pharmacology to prevent stent restenosis. Drugs Aging. 1999;15:341–8.

    Article  PubMed  CAS  Google Scholar 

  4. Hodis HN, Mack WJ, LaBree L, et al. The role of carotid arterial intima-media thickness in predicting clinical coronary events. Ann Intern Med. 1998;128:262–9.

    PubMed  CAS  Google Scholar 

  5. Linhart A, Garlepy J, Massonneau M, et al. Carotid intima-media thickness: the ultimate surrogate end-point of cardiovascular involvement in atherosclerosis. Appl Radiol. 2000;29:25–39.

    Article  Google Scholar 

  6. McNamara DB, Murthy SN, Fonseca AN, et al. Animal models of catheter-induced intimal hyperplasia in type 1 and type 2 diabetes and the effects of pharmacologic intervention. Can J Physiol Pharmacol. 2009;87:37–50.

    Article  PubMed  CAS  Google Scholar 

  7. Mitra AK, Agrawal DK. Gene therapy of fibroproliferative vasculopathies: current ideas in molecular mechanisms and biochemical technology. Pharmacogenomics. 2006;7:1185–98.

    Article  PubMed  CAS  Google Scholar 

  8. Forte A, Della Corte A, De Feo M, et al. Role of myofibroblasts in vascular remodeling; focus on restenosis and aneurysm. Cardiovasc Res. 2010;88:395–405.

    Article  PubMed  CAS  Google Scholar 

  9. Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. J Clin Invest. 2006;116:1793–801.

    Article  PubMed  CAS  Google Scholar 

  10. Newby AC, Zaltsman AB. Molecular mechanisms of intimal hyperplasia. J Pathol. 2000;190:300–9.

    Article  PubMed  CAS  Google Scholar 

  11. Brito L, Amiji M. Nanoparticulate carriers for the treatment of coronary restenosis. Int J Nanomed. 2007;2:143–61.

    Article  CAS  Google Scholar 

  12. Christian T, Verin V, Bochaton-Piallat M, et al. Mechanisms of neointima formation and remodeling in the porcine coronary artery. Circulation. 2001;103:882–8.

    Google Scholar 

  13. Schiller NK, Timothy AM, Aurora HS, et al. A selective somatostatin type-2 receptor agonist inhibits neointimal thickening and enhances endothelial cell growth and morphology following balloon injury in the rabbit. Mol Cell Biochem. 2002;240:31–7.

    Article  PubMed  CAS  Google Scholar 

  14. Jay D, Hitomi H, Griendling KK. Oxidative stress and diabetic cardiovascular complications. Free Radic Biol Med. 2006;40:183–92.

    Article  PubMed  CAS  Google Scholar 

  15. de Simone G, Devereux RB, Chinali M, et al. Diabetes and incident heart failure in hypertensive and normotensive participants of the Strong Heart Study. J Hypertens. 2010;28:353–60.

    Article  PubMed  Google Scholar 

  16. Preis SR, Pencina MJ, Hwang SJ, et al. Trends in cardiovascular disease risk factors in individuals with and without diabetes mellitus in the Framingham Heart Study. Circulation. 2009;120:212–20.

    Article  PubMed  Google Scholar 

  17. Arvanitakis Z, Wilson RS, Bienias J, et al. Diabetes mellitus and risk of Alzheimer’s disease and decline in cognitive function. Arch Neurol. 2004;61:661–6.

    Article  PubMed  Google Scholar 

  18. Wilson PWF, Meigs JB. Cardiometabolic risk: a Framingham perspective. Int J Obes (Lond). 2008;32:S17–20.

    Article  CAS  Google Scholar 

  19. Devici E, Yesil M, Akinci B, et al. Evaluation of insulin resistance in normoglycemic patients with coronary artery disease. Clin Cardiol. 2009;32:32–6.

    Article  Google Scholar 

  20. Elam M, Lovato LC, Ginsberg H. Role of fibrates in cardiovascular disease prevention, the ACCORD-Lipid perspective. Curr Opin Lipidol. 2011;22(1):55–61.

    Article  PubMed  CAS  Google Scholar 

  21. Hamnvik OP, McMahion GT. Glycemic targets for patients with type 2 diabetes mellitus. Mt Sinai J Med. 2009;76:227–33.

    Article  PubMed  Google Scholar 

  22. Meier B. Prevention of restenosis after coronary angioplasty: a pharmacologic approach. Eur Heart J. 1989;10 Suppl G:64–8.

    PubMed  CAS  Google Scholar 

  23. Schlant RC, King SB. Usefulness of calcium entry blockers during and after percutaneous transluminal coronary artery angioplasty. Circulation. 1989;80(6 Suppl):IV 88–92.

    CAS  Google Scholar 

  24. Chesebro JH, Fuster V. Platelet-inhibitor drugs before and after coronary artery bypass surgery and coronary angioplasty: the basis of their use, data from animal studies, clinical trial data, and current recommendations. Cardiology. 1986;73:292–305.

    Article  PubMed  CAS  Google Scholar 

  25. Willis AL, Smith DL. Therapeutic impact of eicosanoids in atherosclerotic disease. Eicosanoids. 1989;2:69–99.

    PubMed  CAS  Google Scholar 

  26. Stein B, Fuster V, Israel DH, et al. Platelet inhibitor agents in cardiovascular disease: an update. J Am Coll Cardiol. 1989;14:813–36.

    Article  PubMed  CAS  Google Scholar 

  27. Baigent C, Blackwell L, Collins R, et al. Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet. 2009;373:1849–60.

    Google Scholar 

  28. Fleischman A, Shoelson SE, Bernier R, et al. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care. 2008;31:289–94.

    Article  PubMed  CAS  Google Scholar 

  29. Chesebro JH, Lam JY, Fuster V. The pathogenesis and prevention of aortocoronary vein bypass graft occlusion and restenosis after arterial angioplasty: role of vascular injury and platelet thrombus deposition. J Am Coll Cardiol. 1986;8(Suppl B):57B–66.

    Article  PubMed  CAS  Google Scholar 

  30. Elwood PC, Gallagher AM, Duthie GG, et al. Aspirin, salicylates and cancer. Lancet. 2009;373:1301–9.

    Article  PubMed  CAS  Google Scholar 

  31. Zimmermann N, Weber AA, Hohlfeld T. Aspirin resistance. Hertz. 2008;33:270–8.

    Google Scholar 

  32. Pignone M, Williams CD. Aspirin for primary prevention of cardiovascular disease in diabetes mellitus. Nat Rev Endocrinol. 2010;6:619–28.

    Article  PubMed  CAS  Google Scholar 

  33. Younis N, Williams S, Ammori B, et al. Role of aspirin in the primary prevention of cardiovascular disease in diabetes mellitus: a meta-analysis. Expert Opin Pharmacother. 2010;11:1459–66.

    Article  PubMed  CAS  Google Scholar 

  34. Ebstein W. Zur therapie des diabetes mellitus, insbesondere uber die anwendung des salicylsauren natron bei demselben. Berl Klin Wochenschr. 1877;24:337–40.

    Google Scholar 

  35. Shoelson S. Invited comment on W Ebstein: on the therapy of diabetes mellitus, in particular the application of sodium salicylate. J Mol Med. 2002;80:618–9.

    Article  Google Scholar 

  36. Yuan M, Konstantanpoulous N, Lee J, et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of IkB. Science. 2001;293:1673–7.

    Article  PubMed  CAS  Google Scholar 

  37. Hundal RS, Peterson KF, Mayerson AB, et al. Mechanism by which high-dose aspirin improves glucose metabolism in type 2 diabetes. J Clin Invest. 2002;109:1321–6.

    PubMed  CAS  Google Scholar 

  38. McCarty MF. Salsalate may have broad utility in the prevention and treatment of vascular disorders and the metabolic syndrome. Med Hypotheses. 2010;75:276–81.

    Article  PubMed  CAS  Google Scholar 

  39. Koska J, Ortega E, Blunt JC. The effect of salsalate on insulin action and glucose tolerance in obese non-diabetic patients: results of a randomized double-blind placebo-controlled study. Diabetologia. 2009;52:385–93.

    Article  PubMed  CAS  Google Scholar 

  40. Tilg H, Moschen AR. Inflammatory mechanisms in the regulation of insulin resistance. Mol Med. 2008;14:222–31.

    Article  PubMed  CAS  Google Scholar 

  41. Pierce GL, Lesniewski LA, Lawson BR, et al. Nulear factor-{kappa}B activation contributes to vascular endothelial dysfunction via oxidative stress in overweight/obese middle-aged and older humans. Circulation. 2009;119:1284–92.

    Article  PubMed  CAS  Google Scholar 

  42. Goldfine AB, Fonseca V, Jablonski KA, et al. TINSAL-T2D (Targeting Inflammation Using Salsalate in Type 2 Diabetes) Study Team. The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Am Int Med. 2010;152:346–57.

    Google Scholar 

  43. Desouza CV, Gerety M, Hamel FG. Neointimal hyperplasia and vascular endothelial growth factor expression are increased in normoglycemic, insulin resistant, obese fatty rats. Atherosclerosis. 2006;184:283–9.

    Article  PubMed  CAS  Google Scholar 

  44. Xinsheng XU, Huixia L, Huili L, et al. Aortic adventitial angiogenesis and lymphogenesis promote intimal inflammation and hyperplasia. Cardiovasc Pathol. 2009;18:269–78.

    Article  Google Scholar 

  45. Stefanadis C, Toutouzas K, Stefanadi E, et al. Inhibition of plaque neovascularization and intimal hyperplasia by specific targeting vascular endothelial growth factor with bevacizumab-eluting stent: an experimental study. Atherosclerosis. 2007;195:269–76.

    Article  PubMed  CAS  Google Scholar 

  46. Novotny NM, Markel TA, Crisostomo PR, et al. Differential IL-6 and VEGF secretions in adult and neonatal mesenchymal stem cells: role of NFkB. Cytokine. 2008;43:215–9.

    Article  PubMed  CAS  Google Scholar 

  47. Murthy SN, Desouza CV, Bost NW, et al. Effects of salsalate therapy on recovery from vascular injury in female Zucker fatty rats. Diabetes. 2010;59:3240–6.

    Article  PubMed  CAS  Google Scholar 

  48. Bray GA. The Zucker-fatty rat: a review. Fed Proc. 1977;36:148–53.

    PubMed  CAS  Google Scholar 

  49. Park SH, Marso SP, Zhongmin Z, et al. Neointimal hyperplasia after arterial injury is increased in a rat model of non-insulin-dependent diabetes mellitus. Circulation. 2001;104:815–9.

    Article  PubMed  CAS  Google Scholar 

  50. Desouza C, Murthy SN, Diez J, et al. Differential effects of peroxisome proliferator activator-alpha and gamma ligands on intimal hyperplasia after balloon catheter-induced injury in Zucker rats. J Cardiovasc Pharmacol Ther. 2003;8:297–305.

    Article  PubMed  CAS  Google Scholar 

  51. Iwakiri Y, Tsai M-H, McCabe TJ, et al. Phosphorylation of eNOS initiates excessive NO production in early phases of portal hypertension. Am J Physiol. 2002;282:H2084–90.

    CAS  Google Scholar 

  52. Goldfine AB, Silver R, Aldhahi W, et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin Transl Sci. 2008;1:36–43.

    Article  PubMed  CAS  Google Scholar 

  53. Walcher D, Marx N. C-Peptide in the vessel wall. Rev Diabet Stud. 2009;6:180–6.

    Article  PubMed  Google Scholar 

  54. Masuda H, Goto M, Tamaoki S, et al. Accelerated intimal hyperplasia and increased endogenous inhibitors for NO synthesis in rabbits with alloxan-induced hyperglycemia. Br J Pharmacol. 1999;126:211–8.

    Article  PubMed  CAS  Google Scholar 

  55. Bode-Boger SM, Martens-Lobenhoffer J, Tager M, et al. Aspirin reduces endothelial cell senescence. Biochem Biophys Res Commun. 2005;334:1226–32.

    Article  PubMed  Google Scholar 

  56. Vaknin-Assa H, Assali A, Lev E, et al. Characterization and clinical outcomes of drug-eluting in-stent restenosis. Isr Med Assoc J. 2010;12:273–6.

    PubMed  Google Scholar 

  57. Ozaki Y, Lemos PA, Yamaguchi T, et al. A quantitative coronary angiography-matched comparison between a prospective randomized multicenter cutting balloon angioplasty and bare metal stent (REDUCE III) and the rapamycin-eluting stent evaluation at Rotterdam Cardiology Hospital (RESEARCH) study. Eurointervention. 2010;6:400–6.

    Article  PubMed  Google Scholar 

  58. Chairman BR, Hadid M, Laddu AA. Choice of initial medical therapy vs. prompt coronary revascularization in patients with type 2 diabetes and stable ischemic coronary artery disease with special emphasis on the BARI 2D trial results. Curr Opin Cardiol. 2010;25:597–602.

    Article  Google Scholar 

Download references

Acknowledgments

This work was supported in part by NIH grants HL 62000 and HL 77421.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Tulane University School of Medicine, New Orleans, LA, USA

    S. N. Murthy, P. J. Kadowitz & D. B. McNamara

Authors
  1. S. N. Murthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. P. J. Kadowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. B. McNamara
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to D. B. McNamara .

Editor information

Editors and Affiliations

  1. St. Boniface General Hospital, Research Centre, Institute of Cardiovascular Sciences, Tache Avenue 351, Winnipeg, R2H 2A6, Manitoba, Canada

    Naranjan S. Dhalla

  2. Jikei University School of Medicine, Shibuya-ku, Ebisu 3-31-6, Tokyo, 150-0013, Japan

    Makoto Nagano

  3. Czech Republic, Institute of Physiology, Academy of Sciences of the, Videnska 1083, Prague, 142 20, Czech Republic

    Bohuslav Ostadal

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Murthy, S.N., Kadowitz, P.J., McNamara, D.B. (2011). Cellular and Molecular Mechanisms Associated with Salicylate Inhibition of Intimal Hyperplasia Following Balloon Catheter-Induced Vascular Injury. In: Dhalla, N., Nagano, M., Ostadal, B. (eds) Molecular Defects in Cardiovascular Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4419-7130-2_22

Download citation

  • DOI: https://doi.org/10.1007/978-1-4419-7130-2_22

  • Published:

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-1-4419-7129-6

  • Online ISBN: 978-1-4419-7130-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation