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Rosuvastatin improves endothelial function in db/db mice: role of angiotensin II type 1 receptors and oxidative stress
Author(s) -
Tian XY,
Wong WT,
Xu A,
Chen ZY,
Lu Y,
Liu LM,
Lee VW,
Lau CW,
Yao X,
Huang Y
Publication year - 2011
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2011.01416.x
Subject(s) - rosuvastatin , endocrinology , medicine , nox4 , nadph oxidase , vasoprotective , nitrotyrosine , angiotensin ii , chemistry , oxidative stress , endothelial dysfunction , reactive oxygen species , endothelium , receptor , nitric oxide , biochemistry , nitric oxide synthase
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 1 R), 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 1 R, 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 1 R‐NAD(P)H oxidase cascade.