title: Improved endothelial function and reduced platelet activation by chronic HMG-CoA-reductase inhibition with rosuvastatin in rats with streptozotocin-induced diabetes mellitus.
abstract: Diabetes is associated with endothelial dysfunction and platelet activation, both of which may contribute to increased cardiovascular risk. We investigated whether the hydroxy-3-methyl-glutaryl CoA reductase inhibitor rosuvastatin improves endothelial function and reduces platelet activation in diabetic rats. Therefore, male Wistar rats were injected with streptozotocin (STZ, 50mg/kg i.v.) to induce insulin-deficient diabetes. Treatment with rosuvastatin (20mg/[kg day]) or vehicle was initiated 2 weeks after injection of STZ and continued for 2 weeks. Thereafter, platelet activation was assessed in fresh whole blood and vascular function was characterized in isolated aortic segments in organ bath chambers. Endothelium-dependent relaxation induced by acetylcholine was significantly attenuated in diabetic rats and improved by treatment with rosuvastatin (maximum relaxation, % of precontraction-control: 99.8+/-0.2, STZ-vehicle: 80.7+/-2.9, STZ-rosuvastatin: 98.9+/-0.7; p<0.01). Similarly, treatment with rosuvastatin significantly reduced fibrinogen-binding to activated GPIIb/IIIa (mean fluorescence-control: 161.0+/-6.9, STZ-vehicle: 207.8+/-15.9, rosuvastatin: 173.6+/-5.3; p<0.05) and P-Selectin surface expression on platelets (mean fluorescence-control: 76.5+/-7.3, STZ-vehicle: 92.1+/-5.5, rosuvastatin: 75.2+/-6.5; p<0.05), while both markers of platelet activation were increased in diabetic rats. Therefore, rosuvastatin treatment normalizes endothelial function and reduces platelet activation in diabetic rats. These effects may contribute to the reduction of cardiovascular events by statins in diabetic patients.
authors.affiliation: Medizinische Klinik und Poliklinik I, Universitätsklinikum Würzburg, Universität Würzburg, Germany. a.schaefer@medizin.uni-wuerzburg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Schäfer
authors.forename: Daniela
authors.initials: D
authors.lastname: Fraccarollo
authors.forename: Christian
authors.initials: C
authors.lastname: Vogt
authors.forename: Ulrike
authors.initials: U
authors.lastname: Flierl
authors.forename: Melinda
authors.initials: M
authors.lastname: Hemberger
authors.forename: Piet
authors.initials: P
authors.lastname: Tas
authors.forename: Georg
authors.initials: G
authors.lastname: Ertl
authors.forename: Johann
authors.initials: J
authors.lastname: Bauersachs
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000201:enzymology / Q000473:pathology*; D004730:Endothelium, Vascular / Q000187:drug effects*; D005464:Fluorobenzenes / Q000494:pharmacology*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism*; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D015539:Platelet Activation / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000068718:Rosuvastatin Calcium; D013311:Streptozocin; D013449:Sulfonamides / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects
chemical_list: D005464:Fluorobenzenes; D011743:Pyrimidines; D013449:Sulfonamides; D013311:Streptozocin; D000068718:Rosuvastatin Calcium; D006903:Hydroxymethylglutaryl CoA Reductases; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III