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Nitropravastatin stimulates reparative neovascularisation and improves recovery from limb Ischaemia in type-1 diabetic mice

Emanueli, Costanza and Monopoli, Angela and Kraenkel, Nicole and Meloni, Marco and Gadau, Sergio Domenico and Campesi, Ilaria and Ongini, Ennio and Madeddu, Paolo Roberto (2007) Nitropravastatin stimulates reparative neovascularisation and improves recovery from limb Ischaemia in type-1 diabetic mice. British Journal of Pharmacology, Vol. 150 (7), p. 873-882. eISSN 1476-5381. Article.

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DOI: 10.1038/sj.bjp.0707142

Abstract

Background and purpose: Mature endothelial cells and their progenitors are dysfunctional in diabetes, resulting in deficient neovascularisation following arterial occlusion. This study aimed to evaluate the therapeutic activity of a nitric oxide (NO) releasing statin in the setting of experimental diabetes and peripheral ischaemia.
Experimental approach: The effects of NCX 6550, an NO-releasing pravastatin derivative, on angiogenesis in ischaemic limbs was studied in normoglycaemic mice or mice made diabetic by treatment with streptozotocin (STZ). Control mice received an equimolar dosage of the parent statin compound, pravastatin. The therapeutic action of NCX 6550 was also tested in mice lacking the gene for endothelial nitric oxide synthase (eNOS).
Key Results: In normoglycaemic or STZ-diabetic CD1 mice, only NCX 6550 stimulated skeletal muscle revascularisation. In addition, NCX 6550 induced greater improvement in limb reperfusion and salvage, than pravastatin. The number of circulating endothelial progenitor cells was decreased in STZ-diabetic mice, this defect being prevented by NCX 6550 and, to a lesser extent by pravastatin. In vitro, high glucose concentrations reduced the migratory capacity of endothelial progenitor EPCs, which was partly reversed by preincubation with pravastatin and completely reversed by NCX 6550. The postischaemic recovery of eNOS knockout mice was severely impaired as a consequence of depressed angiogenesis and this recovery was improved by treatment with NCX 6550, but not with pravastatin.
Conclusions and implications: These findings indicate that incorporation of a bioactive NO moiety improves the therapeutic profile of statins for the treatment of peripheral vascular disease.

Item Type:Article
ID Code:7885
Status:Published
Refereed:Yes
Uncontrolled Keywords:Ischaemia, nitric oxide, statin, diabetes, peripheral vascular disease
Subjects:Area 07 - Scienze agrarie e veterinarie > VET/01 Anatomia degli animali domestici
Divisions:001 Università di Sassari > 01 Dipartimenti > Biologia animale
002 Altri enti e centri di ricerca del Nord Sardegna > National laboratory of the national institute of biostructures and biosystems, Osilo
Publisher:Blackwell / Wiley
eISSN:1476-5381
Copyright Holders:© 2007 Nature Publishing Group
Deposited On:10 Aug 2012 12:28

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