Rosuvastatin improves endothelial function in db/db mice: Role of angiotensin II type 1 receptors and oxidative stress

BACKGROUND AND PURPOSE HMG-CoA reductase inhibitors, statins, with lipid-reducing properties combat against atherosclerosis and diabetes. The favourable modulation of endothelial function may play a significant role in this effect. The present study aimed to investigate the cellular mechanisms responsible for the therapeutic benefits of rosuvastatin in ameliorating diabetes-associated endothelial dysfunction. EXPERIMENTAL APPROACH Twelve-week-old db/db diabetic mice were treated with rosuvastatin at 20 mg·kg ^-1·day ^-1 p.o.for 6 weeks. Isometric force was measured in isolated aortae and renal arteries. Protein expressions including angiotensin II type 1 receptor (AT ₁R), NOX4, p22 ^phox, p67 ^phox, Rac-1, nitrotyrosine, phospho-ERK1/2 and phospho-p38 were determined by Western blotting, while reactive oxygen species (ROS) accumulation in the vascular wall was evaluated by dihydroethidium fluorescence and lucigenin assay. KEY RESULTS Rosuvastatin treatment of db/db mice reversed the impaired ACh-induced endothelium-dependent dilatations in both renal arteries and aortae and prevented the exaggerated contractions to angiotensin II and phenylephrine in db/db mouse renal arteries and aortae. Rosuvastatin reduced the elevated expressions of AT ₁R, p22 ^phox and p67 ^phox, NOX4, Rac1, nitrotyrosine and phosphorylation of ERK1/2 and p38 MAPK and inhibited ROS production in aortae from db/db mice. CONCLUSIONS AND IMPLICATIONS The vasoprotective effects of rosuvastatin are attributed to an increase in NO bioavailability, which is probably achieved by its inhibition of ROS production from the AT ₁R-NAD(P)H oxidase cascade.