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Circulation Research. 2006;98:55-62
Published online before print November 23, 2005, doi: 10.1161/01.RES.0000197842.38758.45
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(Circulation Research. 2006;98:55.)
© 2006 American Heart Association, Inc.

Molecular Medicine

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

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

From the Division of Pathophysiological and Experimental Pathology (M.T., Y.Y., T.F., Y.S., R.-i.K., M.O., S.O., K.S.), Department of Pathology, and Department of Surgery and Science (M.T., Y.S., T.O., Y.M.), Graduate School of Medical Sciences, Kyushu University, Fukuoka; and DNAVEC Corporation (M.I., M.H.), Tsukuba, Ibaraki, Japan.

Correspondence to Yoshikazu Yonemitsu, MD, PhD, Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail yonemitu{at}pathol1.med.kyushu-u.ac.jp

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.


Key Words: diabetic microangiopathy • PDGF-BB • PKC • advanced-glycation end product • pericyte


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