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

Abstract

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.

• Authors: X Y Tian, W T Wong, A Xu, Z Y Chen, Y Lu, L M Liu, V W Lee, C W Lau, X Yao, Y Huang
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 164 Issue 2b Pg. 598-606 (Sep 2011) ISSN: 1476-5381 [Electronic] England
• PMID: 21486274 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Chemical References

• 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

Topics

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