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

Br J Pharmacol. 2011 Sep;164(2b):598-606. doi: 10.1111/j.1476-5381.2011.01416.x.


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 (AT₁R), 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 AT₁R, 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 AT₁R-NAD(P)H oxidase cascade.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiotensin II / metabolism
  • Angiotensin II Type 1 Receptor Blockers / pharmacology
  • Animals
  • Aorta / drug effects
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / metabolism
  • Endothelium, Vascular / physiology*
  • Fluorobenzenes / pharmacology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • NADPH Oxidases / antagonists & inhibitors
  • NADPH Oxidases / genetics
  • NADPH Oxidases / metabolism
  • Nitrogen Oxides / metabolism
  • Oxidative Stress / drug effects*
  • Phenylephrine / metabolism
  • Pyrimidines / pharmacology*
  • Reactive Oxygen Species / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Receptor, Angiotensin, Type 1 / genetics
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Renal Artery / drug effects
  • Rosuvastatin Calcium
  • Signal Transduction / drug effects
  • Sulfonamides / pharmacology*
  • Vasodilation / drug effects


  • Angiotensin II Type 1 Receptor Blockers
  • Fluorobenzenes
  • Nitrogen Oxides
  • Pyrimidines
  • Reactive Oxygen Species
  • Receptor, Angiotensin, Type 1
  • Sulfonamides
  • Angiotensin II
  • Phenylephrine
  • Rosuvastatin Calcium
  • NADPH Oxidases