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: Mitsugu Tanii, Yoshikazu Yonemitsu, Takaaki Fujii, Yasunori Shikada, Ri-ichiro Kohno, Mitsuho Onimaru, Shinji Okano, Makoto Inoue, Mamoru Hasegawa, Toshihiro Onohara, Yoshihiko Maehara, Katsuo Sueishi
• Journal: Circulation research (Circ Res) Vol. 98 Issue 1 Pg. 55-62 (Jan 06 2006) ISSN: 1524-4571 [Electronic] United States
• PMID: 16306442 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inducing Agents
• Glycation End Products, Advanced
• Platelet-Derived Growth Factor
• Proto-Oncogene Proteins c-sis
• Fibroblast Growth Factor 2
• Becaplermin
• Streptozocin
• Protein Kinase C

Topics

• Angiogenesis Inducing Agents (metabolism)
• Animals
• Becaplermin
• Diabetes Mellitus, Experimental (physiopathology)
• Diabetic Angiopathies (etiology, physiopathology)
• Fibroblast Growth Factor 2 (physiology)
• Glycation End Products, Advanced (physiology)
• Hindlimb (blood supply)
• Ischemia (physiopathology)
• Male
• Mice
• Mice, Inbred C57BL
• Neovascularization, Physiologic
• Phosphorylation
• Platelet-Derived Growth Factor (physiology)
• Protein Kinase C (physiology)
• Proto-Oncogene Proteins c-sis
• Streptozocin