Korean Circ J.  2012 Feb;42(2):100-106. 10.4070/kcj.2012.42.2.100.

Higher Plasma Thrombospondin-1 Levels in Patients With Coronary Artery Disease and Diabetes Mellitus

• Choi KY
• Kim DB
• Kim MJ
• Kwon BJ
• Chang SY
• Jang SW
• Cho EJ
• Rho TH
• Kim JH

• KMID: 1826381
• DOI: http://doi.org/10.4070/kcj.2012.42.2.100

Abstract

BACKGROUND AND OBJECTIVES
Thrombospondin-1 (TSP-1) is associated with atherosclerosis in animals with diabetes mellitus (DM). But, no study has investigated the role of TSP-1 in human atherosclerosis. This study investigated the relationship among plasma TSP-1 concentration, DM, and coronary artery disease (CAD).
SUBJECTS AND METHODS
The study involved 374 consecutive subjects with suspected CAD, who had undergone coronary angiography to evaluate effort angina. Patients were divided into four groups as follows: DM(-) and CAD(-), DM(-) and CAD(+), DM(+) and CAD(-), and DM (+) and CAD(+).
RESULTS
We found that plasma TSP-1 levels were higher in patients with DM(+) and CAD(+) (n=103) than those in other patients (n=271) (p<0.01). A multivariate analysis showed that male gender {odds ratio (OR), 2.728; 95% confidence interval (CI), 1.035-7.187}, high density lipoprotein-cholesterol (OR, 0.925; 95% CI, 0.874-0.980), glycated hemoglobin (OR, 1.373; 95% CI, 1.037-1.817), and plasma TSP-1 (OR, 1.004; 95% CI, 1.000-1.008) levels were independently associated with the presence of CAD in patients with DM.
CONCLUSION
Plasma TSP-1 levels were higher in patients with DM(+) and CAD(+) than those in other patients, and plasma TSP-1 levels were independently associated with the presence of CAD in patients with DM. These findings show a possible link between human plasma TSP-1 concentration and CAD in patients with DM.

Keyword

Thrombospondin-1; Coronary artery disease; Diabetes mellitus

MeSH Terms

Aluminum Hydroxide
Animals
Atherosclerosis
Carbonates
Coronary Angiography
Coronary Artery Disease
Coronary Vessels
Diabetes Mellitus
Hemoglobins
Humans
Male
Multivariate Analysis
Plasma
Thrombospondin 1
Aluminum Hydroxide
Carbonates
Hemoglobins
Thrombospondin 1

Figure

• 

  Fig. 1 Comparison of plasma thrombospondin-1 (TSP-1) levels. A: patients were divided into four groups to compare plasma TSP-1 levels. Statistical analysis showed that TSP-1 levels were highest in the DM(+)CAD(+) group. B: when patients were divided into two groups according to the presence of DM, plasma levels of TSP-1 were higher in the DM group than those in the non-DM group (577.9±104.5 ng/mL vs. 519.3±123.5 ng/mL, p<0.001). C: when patients were divided into two groups according to CAD, plasma levels of TSP-1 were not significantly different between the non-CAD and CAD groups (532.4±117.0 ng/mL vs. 552.7±120.2 ng/mL, p=0.091). DM(-)CAD(-): patients without DM and without CAD, DM(-)CAD(+): patients without DM and with CAD, DM(+)CAD(-): patients with DM but without CAD, DM(+)CAD(+): patients with DM and CAD, TSP-1: thrombospodin-1, DM: diabetes mellitus, CAD: coronary artery disease.

Reference

1. Baenziger NL, Brodie GN, Majerus PW. A thrombin-sensitive protein of human platelet membranes. Proc Natl Acad Sci U S A. 1971. 68:240–243.

2. Bornstein P. Diversity of function is inherent in matricellular proteins: an appraisal of thrombospondin 1. J Cell BIol. 1995. 130:503–506.

3. Adams JC. Thrombospondins: multifunctional regulators of cell interactions. Annu Rev Cell Dev Biol. 2001. 17:25–51.

4. Ren B, Yee KO, Lawler J, Khosravi-Far R. Regulation of tumor angiogenesis by thrombospondin-1. Biochim Biophys Acta. 2006. 1765:178–188.

5. Agah A, Kyriakides TR, Lawler J, Bornstein P. The lack of thrombospondin-1 (TSP1) dictates the course of wound healing in double-TSP1/TSP2-null mice. Am J Pathol. 2002. 161:831–839.

6. Frangogiannis NG, Ren G, Dewald O, et al. Critical role of endogenous thrombospondin-1 in preventing expansion of healing myocardial infarcts. Circulation. 2005. 111:2935–2942.

7. Isenberg JS, Romeo MJ, Abu-Asab M, et al. Increasing survival of ischemic tissue by targeting CD47. Circ Res. 2007. 100:712–720.

8. Stenina OI, Krukovets I, Wang K, et al. Increased expression of thrombospondin-1 in vessel wall of diabetic zucker rat. Circulation. 2003. 107:3209–3215.

9. Raman P, Krukovets I, Marinic TE, Bornstein P, Stenina OI. Glycosylation mediates up-regulation of a potent antiangiogenic and proatherogenic protein, thrombospondin-1, by glucose in vascular smooth muscle cells. J Biol Chem. 2007. 282:5704–5714.

10. Murphy M, Godson C, Cannon S, et al. Suppression subtractive hybridization identifies high glucose levels as a stimulus for expression of connective tissue growth factor and other genes in human mesangial cells. J Biol Chem. 1999. 274:5830–5834.

11. Tada H, Kawai H, Ishii H, Nomura K, Urayama T, Isogai S. Thrombospondin modulates adhesion, proliferation and production of extracellular matrix in mesangial cells. Tohoku J Exp Med. 1995. 177:293–302.

12. Poczatek MH, Hugo C, Darley-Usmar V, Murphy-Ullrich JE. Glucose stimulation of transforming growth factor-beta bioactivity in mesangial cells is mediated by thrombospondin-1. Am J Pathol. 2000. 157:1353–1363.

13. Yevdokimova N, Wahab NA, Mason RM. Thrombospondin-1 is the key activator of TGF-beta1 in human mesangial cells exposed to high glucose. J Am Soc Nephrol. 2001. 12:703–712.

14. Belmadani S, Bernal J, Wei CC, et al. A thrombospondin-1 antagonist of transforming growth factor-beta activation blocks cardiomyopathy in rats with diabetes and elevated angiotensin II. Am J Pathol. 2007. 171:777–789.

15. Report of the Expert Committee on the diagnosis and classification of diabetes mellitus. Diabetes care. 1997. 20:1183–1197.

16. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003. 289:2560–2572.

17. Gensini GG. A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol. 1983. 51:606.

18. Majack RA, Goodman LV, Dixit VM. Cell surface thrombospondin is functionally essential for vascular smooth muscle cell proliferation. J Cell Biol. 1988. 106:415–422.

19. Stouffer GA, Hu Z, Sajid M, et al. Beta3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells. Circulation. 1998. 97:907–915.

20. Kirma C, Akcakoyun M, Esen AM, et al. Relationship between endothelial function and coronary risk factors in patients with stable coronary artery disease. Circ J. 2007. 71:698–702.

21. Hsu SC, Volpert OV, Steck PA, et al. Inhibition of angiogenesis in human glioblastomas by chromosome 10 induction of thrombospondin-1. Cancer Res. 1996. 56:5684–5691.

22. Nör JE, Mitra RS, Sutorik MM, Mooney DJ, Castle VP, Polverini PJ. Thrombospondin-1 induces endothelial cell apoptosis and inhibits angiogenesis by activating the caspase death pathway. J Vasc Res. 2000. 37:209–218.

23. McGillicuddy FC, O'Toole D, Hickey JA, Gallagher WM, Dawson KA, Keenan AK. TGF-beta1-induced thrombospondin-1 expression through the p38 MAPK pathway is abolished by fluvastatin in human coronary artery smooth muscle cells. Vascul Pharmacol. 2006. 44:469–475.

24. Topol EJ, McCarthy J, Gabriel S, et al. Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation. 2001. 104:2641–2644.

25. Yamada Y, Izawa H, Ichihara S, et al. Prediction of the risk of myocardial infarction from polymorphisms in candidate genes. N Engl J Med. 2002. 347:1916–1923.

26. Carlson CB, Liu Y, Keck JL, Mosher DF. Influences of the N700S thrombospondin-1 polymorphism on protein structure and stability. J Biol Chem. 2008. 283:20069–20076.

27. Stenina OI. Regulation of vascular genes by glucose. Curr Pharm Des. 2005. 11:2367–2381.

28. Selvin E, Marinopoulos S, Berkenblit G, et al. Meta-analysis: glycosylated hemoglobin and cardiovascular disease in diabetes mellitus. Ann Intern Med. 2004. 141:421–431.