Statins restore ischemic limb blood flow in diabetic microangiopathy via eNOS/NO upregulation but not via PDGF-BB expression.
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(omega)-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.
Fujii
Takaaki
T
Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.
Onimaru
Mitsuho
M
Yonemitsu
Yoshikazu
Y
Kuwano
Hiroyuki
H
Sueishi
Katsuo
K
D000818:Animals; D000077214:Becaplermin; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D008078:Cholesterol, LDL / Q000097:blood; D003131:Combined Modality Therapy; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D017719:Diabetic Foot / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015316:Genetic Therapy / Q000379:methods; D017127:Glycation End Products, Advanced / Q000097:blood; D006614:Hindlimb; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D007511:Ischemia / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects* / Q000201:enzymology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III; D010982:Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism; D017035:Pravastatin / Q000494:pharmacology; D020574:Proto-Oncogene Proteins c-sis; D011804:Quinolines / Q000494:pharmacology; D012039:Regional Blood Flow; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D015854:Up-Regulation
D001786:Blood Glucose; D008078:Cholesterol, LDL; D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D011804:Quinolines; D000077214:Becaplermin; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D017035:Pravastatin; C108475:pitavastatin; D019331:NG-Nitroarginine Methyl Ester