Introduction. The aim of this study was to investigate the effect of bezafibrate as a pan-PPAR agonist on angiogenesis and serum nitrite, the main metabolite of nitric oxide (NO), vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) concentrations in hindlimb ischemia model of normal and type I diabetic rats. Methods. 28 male Wistar rats were divided into control and diabetic groups. Then, all rats underwent unilateral hindlimb ischemia. After recovery, they were randomly assigned to one of the following experimental groups: (1) control; (2) control？+？bezafibrate (400？mg/kg/day); (3) diabetic; (4) diabetic？+？beztafibrate. After three weeks, blood samples were taken and capillary density was evaluated in the gasterocnemius muscle of ischemic limb. Results. Bezafibrate increased capillary density and capillary/fiber ratio in ischemic leg of diabetic and control rats ( ). Serum VEGF and VEGFR-2 concentrations did not alter after bezafibrate administration, however, serum nitrite concentration was significantly higher in bezafibrate-treated groups than non-treated groups ( ). Discussion. It seems that bezafibrate, as a pan PPAR agonist, restores angiogenesis in hindlimb ischemic diabetic animals and is useful for prevention and/or treatment of peripheral artery disease in diabetic subjects. 1. Introduction Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that regulate expression of genes involved in some biological effects including lipid metabolism, inflammatory responses, and glucose homeostasis [1]. There are three isotypes of PPAR superfamily: PPARα, PPARβ, and PPARγ. Today, PPAR agonists have clinical importance in management of dyslipidemia (such as clofibrate, a PPARα agonist) and reducing insulin resistance and antidiabetic activity (such as rosiglitazone, a PPARγ agonist). Bezafibrate, a PPARα agonist, is high-affinity ligand of PPARγ and PPARβ and is considered as a pan-PPAR agonist [2, 3]. Bezafibrate is more efficient in reducing body weight and blood glucose than fenofibrate in overweight mice fed with high-fat diet [4]. It also raises HDL, reduces triglyceride, and improves insulin sensitivity in diabetic subjects [5, 6]. Diabetes is associated with several cardiovascular abnormalities including abnormal angiogenesis [7]. Enhanced or insufficient angiogenesis plays a role in some complications of diabetes including diabetic retinopathy or impaired wound healing, respectively [8]. In recent years, it is suggested that PPARs may be involved in regulating angiogenesis [9]; however,
References
[1]
B. Desvergne and W. Wahli, “Peroxisome proliferator-activated receptors: nuclear control of metabolism,” Endocrine Reviews, vol. 20, no. 5, pp. 649–688, 1999.
[2]
T. M. Willson, P. J. Brown, D. D. Sternbach, and B. R. Henke, “The PPARs: from orphan receptors to drug discovery,” Journal of Medicinal Chemistry, vol. 43, no. 4, pp. 527–550, 2000.
[3]
A. Tenenbaum, M. Motro, and E. Z. Fisman, “Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons,” Cardiovascular Diabetology, vol. 4, p. 14, 2005.
[4]
C. Fernandes-Santos, R. E. Carneiro, L. de Souza Mendonca, M. B. Aguila, and C. A. Mandarim-de-Lacerda, “Pan-PPAR agonist beneficial effects in overweight mice fed a high-fat high-sucrose diet,” Nutrition, vol. 25, no. 7-8, pp. 818–827, 2009.
[5]
A. Tenenbaum, M. Motro, E. Z. Fisman et al., “Effect of bezafibrate on incidence of type 2 diabetes mellitus in obese patients,” European Heart Journal, vol. 26, no. 19, pp. 2032–2038, 2005.
[6]
A. Tenenbaum, E. Z. Fisman, V. Boyko et al., “Attenuation of progression of insulin resistance in patients with coronary artery disease by bezafibrate,” Archives of Internal Medicine, vol. 166, no. 7, pp. 737–741, 2006.
[7]
M. Simons, “Angiogenesis, arteriogenesis, and diabetes: paradigm reassessed?” Journal of the American College of Cardiology, vol. 46, no. 5, pp. 835–837, 2005.
[8]
M. Simons, “Angiogenesis: where do we stand now?” Circulation, vol. 111, no. 12, pp. 1556–1566, 2005.
[9]
F. Biscetti, G. Straface, D. Pitocco, F. Zaccardi, G. Ghirlanda, and A. Flex, “Peroxisome proliferator-activated receptors and angiogenesis,” Nutrition, Metabolism and Cardiovascular Diseases, vol. 19, no. 11, pp. 751–759, 2009.
[10]
P. Carmeliet, “Angiogenesis in health and disease,” Nature Medicine, vol. 9, no. 6, pp. 653–660, 2003.
[11]
N. Ferrara, “Vascular endothelial growth factor,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 29, no. 6, pp. 789–791, 2009.
[12]
R. S. Kerbel, “Tumor angiogenesis,” New England Journal of Medicine, vol. 358, no. 19, pp. 2039–2049, 2008.
[13]
J. P. Cook, “NO and angiogenesis,” Atherosclerosis Supplements, vol. 4, no. 4, pp. 53–60, 2003.
[14]
C. D. Luque, H. Vargas Robles, E. Romo, A. Rios, and B. Escalante, “The role of nitric oxide in the post-ischemic revascularization process,” Pharmacology and Therapeutics, vol. 112, no. 2, pp. 553–563, 2006.
[15]
Y. Taniyama, R. Morishita, M. Aoki et al., “Therapeutic angiogenesis induced by human hepatocyte growth factor gene in rat and rabbit hindlimb ischemia models: preclinical study for treatment of peripheral arterial disease,” Gene Therapy, vol. 8, no. 3, pp. 181–189, 2001.
[16]
T. Murohara, T. Asahara, M. Silver et al., “Nitric oxide synthase modulates angiogenesis in response to tissue ischemia,” Journal of Clinical Investigation, vol. 101, no. 11, pp. 2567–2578, 1998.
[17]
A. Katayama, Y. Yamamoto, K. Tanaka et al., “Fenofibrate enhances neovascularization in a murine ischemic hindlimb model,” Journal of Cardiovascular Pharmacology, vol. 54, no. 5, pp. 399–404, 2009.
[18]
D. Panigrahy, A. Kaipainen, S. Huang et al., “PPARα agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 3, pp. 985–990, 2008.
[19]
J. A. Beckman, M. A. Creager, and P. Libby, “Diabetes and atherosclerosis epidemiology, pathophysiology, and management,” Journal of the American Medical Association, vol. 287, no. 19, pp. 2570–2581, 2002.
[20]
N. Ferrara, “Vascular endothelial growth factor: molecular and biological aspects,” Current Topics in Microbiology and Immunology, vol. 237, pp. 1–30, 1999.
[21]
P. Carmeliet, “Mechanisms of angiogenesis and arteriogenesis,” Nature Medicine, vol. 6, no. 4, pp. 389–395, 2000.
[22]
K. Kawasaki, R. S. Smith Jr, C. M. Hsieh, J. Sun, J. Chao, and J. K. Liao, “Activation of the phosphatidylinositol 3-kinase/protein kinase Akt pathway mediates nitric oxide-induced endothelial cell migration and angiogenesis,” Molecular and Cellular Biology, vol. 23, no. 16, pp. 5726–5737, 2003.
[23]
T. Murohara, B. Witzenbichler, I. Spyridopoulos et al., “Role of endothelial nitric oxide synthase in endothelial cell migration,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 19, no. 5, pp. 1156–1161, 1999.
[24]
D. Fukumura, T. Gohongi, A. Kadambi et al., “Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability,” Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 5, pp. 2604–2609, 2001.
[25]
A. Pozzi and J. V. Capdevila, “PPARalpha ligands as antitumorigenic and antiangiogenic agents,” PPAR Research, vol. 2008, Article ID 906542, 8 pages, 2008.
[26]
D. Bishop-Bailey, “Peroxisome proliferator-activated receptor beta/delta goes vascular,” Circulation Research, vol. 102, no. 2, pp. 146–147, 2008.
[27]
R. S. Elkeles, J. R. Diamond, C. Poulter et al., “Cardiovascular outcomes in type 2 diabetes: a double-blind placebo- controlled study of bezafibrate: the St. Mary's, Ealing, Northwick Park diabetes cardiovascular disease prevention (SENDCAP) study,” Diabetes Care, vol. 21, no. 4, pp. 641–648, 1998.
[28]
C. G. Ericsson, J. Nilsson, L. Grip, B. Svane, and A. Hamsten, “Effect of bezafibrate treatment over five years on coronary plaques causing 20% to 50% diameter narrowing (The Bezafibrate Coronary Atherosclerosis Intervention Trial [BECAIT]),” American Journal of Cardiology, vol. 80, no. 9, pp. 1125–1129, 1997.
[29]
F. Biscetti, E. Gaetani, A. Flex et al., “Selective activation of peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma induces neoangiogenesis through a vascular endothelial growth factor-dependent mechanism,” Diabetes, vol. 57, no. 5, pp. 1394–1404, 2008.
