Antioxidant and antiplatelet effects of rosuvastatin in a hamster model of prediabetes.
The objectives of this study were to determine the relationships among Type II diabetes (T2DM)-dependent elevations in platelet-derived reactive oxygen species (ROS), platelet-surface protein disulfide isomerase (psPDI) NO-releasing activity, and platelet aggregation and to evaluate the efficacy of rosuvastatin in normalizing these parameters in primary cells derived from a hamster model of prediabetic insulin resistance induced by fructose feeding. Platelets from rosuvastatin-treated non-fructose-fed (NFF) and fructose-fed (FF) hamsters were analyzed for aggregability and psPDI-denitrosation activity. Platelets from NFF animals treated with xanthine/xanthine oxidase (X/XO) were assessed for the same parameters and primary aortic endothelial cells (AEC) cultivated with a range of [rosuvastatin] +/- mevalonate were analyzed for ROS production. Platelets from FF hamsters displayed statistically significant enhanced ROS production, diminished psPDI-mediated NO-releasing activity, and hyperaggregability. Suggestively, platelets from NFF animals treated with X/XO displayed characteristics similar to platelets from FF animals. Rosuvastatin elicited a normalizing effect on all parameters measured in platelets from FF animals. Further, ROS production in primary AEC from FF animals could be blunted to that of NFF animals by concentrations of rosuvastatin in the range of those achieved in the bloodstream. Diminished psPDI-dependent NO-releasing activity and increased initial aggregation rates of FF platelets may result from elevated vascular ROS production under conditions of insulin resistance. Normalization of ROS production and platelet aggregation by rosuvastatin indicates its potential use as a vasculoprotective agent.
Miersch
Shane
S
Department of Chemistry and Biochemistry, University of Windsor, 401 Sunset Avenue, Windsor, Ontario, Canada N9B 3P4.
Sliskovic
Inga
I
Raturi
Arun
A
Mutus
Bulent
B
D000818:Animals; D000975:Antioxidants; D001792:Blood Platelets / Q000187:drug effects*; D006224:Cricetinae; D003924:Diabetes Mellitus, Type 2 / Q000517:prevention & control*; D005464:Fluorobenzenes / Q000494:pharmacology*; D005632:Fructose / Q000009:adverse effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D008647:Mesocricetus; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D011236:Prediabetic State / Q000188:drug therapy*; D019704:Protein Disulfide-Isomerases / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*
D000975:Antioxidants; D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D013449:Sulfonamides; D005632:Fructose; D009569:Nitric Oxide; D000068718:Rosuvastatin Calcium; D019704:Protein Disulfide-Isomerases