title: Diabetic microangiopathy in ischemic limb is a disease of disturbance of the platelet-derived growth factor-BB/protein kinase C axis but not of impaired expression of angiogenic factors.
abstract: Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-alpha and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.
authors.affiliation: Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Tanii
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yonemitsu
authors.forename: Takaaki
authors.initials: T
authors.lastname: Fujii
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Shikada
authors.forename: Ri-ichiro
authors.initials: R
authors.lastname: Kohno
authors.forename: Mitsuho
authors.initials: M
authors.lastname: Onimaru
authors.forename: Shinji
authors.initials: S
authors.lastname: Okano
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Mamoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Onohara
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Maehara
authors.forename: Katsuo
authors.initials: K
authors.lastname: Sueishi
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D000077214:Becaplermin; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000503:physiopathology; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D017127:Glycation End Products, Advanced / Q000502:physiology; D006614:Hindlimb / Q000098:blood supply*; D007511:Ischemia / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology*; D020574:Proto-Oncogene Proteins c-sis; D013311:Streptozocin
chemical_list: D043925:Angiogenesis Inducing Agents; D017127:Glycation End Products, Advanced; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016222:Fibroblast Growth Factor 2; D000077214:Becaplermin; D013311:Streptozocin; D011493:Protein Kinase C