HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 294/6/H2785    most recent 00149.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Fujii, T. Articles by Sueishi, K. PubMed PubMed Citation Articles by Fujii, T. Articles by Sueishi, K.

Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression

¹Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka; ²Department of Gene Therapy, Graduate School of Medicine, Chiba University, Chiba; and ³Department of General Surgical Science, Graduate School of Medicine, Gunma University, Gunma, Japan

Submitted 12 February 2008 ; accepted in final form 11 April 2008

3-Hydroxy-3-methyl-glutaryl CoA reductase inhibitors, or statins, have pleiotropic effects and can protect the vasculature in a manner independent of their lipid-lowering effect. The effectiveness of statins in reducing the risk of coronary events has been shown even in patients with diabetes, and their effects on diabetic complications have been reported. Using a model of severe hindlimb ischemia in streptozotocin-induced diabetic mice (STZ-DM), we investigated the effects and mechanisms of statin therapy in diabetic angiopathy in ischemic hindlimbs. As a result, STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Supplementation with statins significantly prevented autoamputation. We previously showed that diabetic vascular complications are caused by impaired expression of PDGF-BB, but statin therapy did not enhance PDGF-BB expression. Statins helped enhance endogenous endothelial nitric oxide (NO) synthase (eNOS) expression. Furthermore, the inhibition of NO synthesis by the administration of N-nitro-L-arginine methyl ester impaired the ability of statins to prevent STZ-DM mouse limb autoamputation, indicating that the therapeutic effect of statins in hindlimb ischemia in STZ-DM mice occurs via the eNOS/NO pathway. A combination therapy of statins and PDGF-BB gene supplementation was more effective for diabetic angiopathy than either therapy alone. In conclusion, these findings indicate that statin therapy might be useful for preventing intractable diabetic foot disease in patients with diabetic angiopathy.

endothelial nitric oxide synthase; nitric oxide; platelet-derived growth factor-BB; diabetes mellitus