Role of GW0742 A PPARβ/δ Agonist on Coronary Angiogenesis in Control and Diabetic Rats

Document Type : Original Article (s)

Authors

1 MSc Student, Student Research Committee, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

2 Associate Professor, Department of Physiology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

3 Assistant Professor, Department of Anatomy, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

Background: Peroxisome proliferator activated receptors (PPARs) are ligand activated transcription factors; comprising of three isoforms in human: PPARβ/δ, PPARγ and PPARα. Since PPARs affect on cytokines and growth factors, it is suggested that PPARs may be regulated angiogenesis process. In this study, we investigated the hypothesis that activation of PPARβ /δ by GW0742 can restore coronary angiogenesis in diabetic and control rats.Methods: Twenty-four male rats were randomly divided into four groups. For induction of diabetes we used streptozotocin (50 mg/kg). The groups were as follows: group 1: control rats were given placebo, group 2: control rats were given GW0742 (1 mg/kg/day) subcutaneously, group 3: diabetic rats were given placebo and group 4: diabetic rats were given GW0742 (1 mg/kg/day) subcutaneously. After 21 days capillary density was evaluated in cardiac muscle by immunohistochemistry.Findings: The mean capillary density in cardiac muscles of diabetic rats were lower than control (P = 0.08). GW0742 administration could restore capillary density of the heart in diabetic rats (215.82 ± 11.3 versus121.71 ± 13.32 number of capillaries per mm2) while could not alter capillary density in control rats (156.3 ± 8.97 versus 153.78 ± 11.08 number of capillaries per mm2).  Conclusion: this study showed that diabetes is associated by reduced capillary density in the heart. PPARβ/δ activation by GW0742 could restore coronary angiogenesis in diabetic rats while did not change angiogenesis in non diabetic rats. 

Keywords

References

  1. Yki-Jarvinen H. Thiazolidinediones. N Engl J Med 2004; 351(11): 1106-18.
  2. Touyz RM, Schiffrin EL. Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications. Vascul Pharmacol 2006; 45(1): 19-28.
  3. Pozzi A, Capdevila JH. PPARalpha Ligands as Antitumorigenic and Antiangiogenic Agents. PPAR Res 2008; 2008: 906542.
  4. Schmidt A, Vogel RL, Witherup KM, Rutledge SJ, Pitzenberger SM, Adam M, et al. Identification of fatty acid methyl ester as naturally occurring transcriptional regulators of the members of the peroxisome proliferator-activated receptor family. Lipids 1996; 31(11): 1115-24.
  5. Xu HE, Lambert MH, Montana VG, Parks DJ, Blanchard SG, Brown PJ, et al. Molecular recognition of fatty acids by peroxisome proliferator-activated receptors. Mol Cell 1999; 3(3): 397-403.
  6. Wang N. PPAR-delta in Vascular Pathophysiology. PPAR Res 2008; 2008: 164163.
  7. Kliewer SA, Forman BM, Blumberg B, Ong ES, Borgmeyer U, Mangelsdorf DJ, et al. Differential expression and activation of a family of murine peroxisome proliferator-activated receptors. Proc Natl Acad Sci U S A 1994; 91(15): 7355-9.
  8. Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator-activated receptors alpha and delta. Proc Natl Acad Sci U S A 1997; 94(9): 4312-7.
  9. Lee CH, Chawla A, Urbiztondo N, Liao D, Boisvert WA, Evans RM, et al. Transcriptional repression of atherogenic inflammation: modulation by PPARdelta. Science 2003; 302(5644): 453-7.
  10. Rivard A, Silver M, Chen D, Kearney M, Magner M, Annex B, et al. Rescue of diabetes-related impairment of angiogenesis by intramuscular gene therapy with adeno-VEGF. Am J Pathol 1999; 154(2): 255-63.
  11. Wagner N, Jehl-Pietri C, Lopez P, Murdaca J, Giordano C, Schwartz C, et al. Peroxisome proliferator-activated receptor beta stimulation induces rapid cardiac growth and angiogenesis via direct activation of calcineurin. Cardiovasc Res 2009; 3(1): 61-71.
  12. Jacobi J, Porst M, Cordasic N, Namer B, Schmieder RE, Eckardt KU, et al. Subtotal nephrectomy impairs ischemia-induced angiogenesis and hindlimb re-perfusion in rats. Kidney Int 2006; 69(11): 2013-21.
  13. Carmeliet P. Angiogenesis in health and disease. Nature Medicine 2003; 9: 653-60.
  14. Simons M. Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed? J Am Coll Cardiol 2005; 46(5): 835-7.
  15. Kivela R, Silvennoinen M, Lehti M, Jalava S, Vihko V, Kainulainen H. Exercise-induced expression of angiogenic growth factors in skeletal muscle and in capillaries of healthy and diabetic mice. Cardiovasc Diabetol 2008; 7: 13.
  16. Ebrahimian TG, Tamarat R, Clergue M, Duriez M, Levy BI, Silvestre JS. Dual effect of angiotensin-converting enzyme inhibition on angiogenesis in type 1 diabetic mice. Arterioscler Thromb Vasc Biol 2005; 25(1): 65-70.
  17. Gao L, Yu DM. Molecular mechanism of limbs' postischemic revascularization improved by perindopril in diabetic rats. Chin Med J (Engl ) 2008; 121(21): 2129-33.
  18. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, et al. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 2002; 105(3): 373-9.
  19. Hazarika S, Dokun AO, Li Y, Popel AS, Kontos CD, Annex BH. Impaired angiogenesis after hindlimb ischemia in type 2 diabetes mellitus: differential regulation of vascular endothelial growth factor receptor 1 and soluble vascular endothelial growth factor receptor 1. Circ Res 2007; 101(9): 948-56.
  20. Sasso FC, Torella D, Carbonara O, Ellison GM, Torella M, Scardone M, et al. Increased vascular endothelial growth factor expression but impaired vascular endothelial growth factor receptor signaling in the myocardium of type 2 diabetic patients with chronic coronary heart disease. J Am Coll Cardiol 2005; 46(5): 827-34.
  21. Waltenberger J, Lange J, Kranz A. Vascular endothelial growth factor-A-induced chemotaxis of monocytes is attenuated in patients with diabetes mellitus: A potential predictor for the individual capacity to develop collaterals. Circulation 2000; 102(2): 185-90.
  22. Rubenstrunk A, Hanf R, Hum DW, Fruchart JC, Staels B. Safety issues and prospects for future generations of PPAR modulators. Biochim Biophys Acta 2007; 1771(8): 1065-81.
  23. Bishop-Bailey D. Peroxisome proliferator-activated receptor beta/delta goes vascular. Circ Res 2008; 102(2): 146-7.
  24. Biscett F, Straface G, Pitocco D, Zaccardi F, Ghirlanda G, Flex A. Peroxisome proliferator-activated receptors and angiogenesis. Nutrition, Metabolism & Cardiovascular Diseases 2009; 19(11): 751-9.
  25. Muller-Brusselbach S, Komhoff M, Rieck M, Meissner W, Kaddatz K, Adamkiewicz J, et al. Deregulation of tumor angiogenesis and blockade of tumor growth in PPARbeta-deficient mice. EMBO J 2007; 26(15): 3686-98.
  26. Gaudel C, Schwartz C, Giordano C, Abumrad NA, Grimaldi PA. Pharmacological activation of PPARbeta promotes rapid and calcineurin-dependent fiber remodeling and angiogenesis in mouse skeletal muscle. Am J Physiol Endocrinol Metab 2008; 295(2): E297-E304.
  27. Piqueras L, Reynolds AR, Hodivala-Dilke KM, Alfranca A, Redondo JM, Hatae T, et al. Activation of PPARbeta/delta induces endothelial cell proliferation and angiogenesis. Arterioscler Thromb Vasc Biol 2007; 27(1): 63-9.
  28. Marin HE, Peraza MA, Billin AN, Willson TM, Ward JM, Kennett MJ, et al. Ligand activation of peroxisome proliferator-activated receptor beta inhibits colon carcinogenesis. Cancer Res 2006; 66(8): 4394-401.
Journal of Isfahan Medical School
Volume 29, Issue 145 - Serial Number 145
May and June 2011
Pages 861-868

Files

History

  • Receive Date: 18 July 2011
  • Revise Date: 01 November 2024
  • Accept Date: 06 April 2022

Share

How to cite

Statistics