title: Rosuvastatin improves endothelial function in db/db mice: role of angiotensin II type 1 receptors and oxidative stress.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, School of Biomedical Sciences, Hong Kong, China.
authors.forename: X Y
authors.initials: XY
authors.lastname: Tian
authors.forename: W T
authors.initials: WT
authors.lastname: Wong
authors.forename: A
authors.initials: A
authors.lastname: Xu
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Chen
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: L M
authors.initials: LM
authors.lastname: Liu
authors.forename: V W
authors.initials: VW
authors.lastname: Lee
authors.forename: C W
authors.initials: CW
authors.lastname: Lau
authors.forename: X
authors.initials: X
authors.lastname: Yao
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D005464:Fluorobenzenes / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009589:Nitrogen Oxides / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010656:Phenylephrine / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects; D000068718:Rosuvastatin Calcium; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D014664:Vasodilation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D005464:Fluorobenzenes; D009589:Nitrogen Oxides; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D044140:Receptor, Angiotensin, Type 1; D013449:Sulfonamides; D000804:Angiotensin II; D010656:Phenylephrine; D000068718:Rosuvastatin Calcium; D019255:NADPH Oxidases