title: Cilostazol improves the response to ischemia in diabetic mice by a mechanism dependent on PPARγ.
abstract: Cilostazol is effective for the treatment of peripheral ischemia. This compound has several beneficial effects on platelet aggregation, serum lipids and endothelial cells, and we recently found that it enhances collateral blood flow in the ischemic hind limbs of mice. Peroxisome proliferator-activated receptor (PPAR)γ, a receptor for thiazolidinediones, plays a role in angiogenesis. The aim of this work was to investigate the underlying molecular mechanisms and effects of cilostazol in a model of peripheral ischemia in diabetic mice. We induced diabetes in mice by streptozotocin (STZ) administration and studied ischemia-induced angiogenesis in the ischemic hind limbs of cilostazol-treated and untreated control mice. We found that perfusion recovery was significantly improved in treated compared with control diabetic mice. Interestingly, we found that the expression of PPARγ is reduced in ischemic tissues of diabetic mice. Furthermore, we discovered that local inhibition of the activity of this nuclear receptor decreased the angiogenic response to cilostazol treatment. Finally, we noted that this phenomenon is dependent on VEGF and modulated by PPARγ. Cilostazol administration enhances collateral blood flow in the ischemic hind limbs of STZ-induced diabetic mice through a PPARγ-dependent mechanism.
authors.affiliation: Laboratory of Vascular Biology and Genetics, Department of Medicine, A. Gemelli University Hospital, Catholic University School of Medicine, Rome, Italy; Division of Rheumatology, Institute of Rheumatology & Affine Sciences, Catholic University School of Medicine, Rome, Italy. Electronic address: f.biscetti@gmail.com.
authors.forename: Federico
authors.initials: F
authors.lastname: Biscetti
authors.forename: Giovanni
authors.initials: G
authors.lastname: Pecorini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Arena
authors.forename: Egidio
authors.initials: E
authors.lastname: Stigliano
authors.forename: Flavia
authors.initials: F
authors.lastname: Angelini
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ghirlanda
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Ferraccioli
authors.forename: Andrea
authors.initials: A
authors.lastname: Flex
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000494:pharmacology*; D000818:Animals; D000077407:Cilostazol; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000503:physiopathology*; D006614:Hindlimb / Q000098:blood supply / Q000187:drug effects; D007511:Ischemia / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic / Q000187:drug effects; D047495:PPAR gamma / Q000378:metabolism*; D012039:Regional Blood Flow / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D043925:Angiogenesis Inducing Agents; D047495:PPAR gamma; D013777:Tetrazoles; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D000077407:Cilostazol
keywords: Angiogenesis; Cilostazol; Diabetes; PPARγ; Peroxisome proliferator-activated receptor