BACKGROUND AND PURPOSEHMG-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 APPROACHTwelve-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 RESULTSRosuvastatin 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 IMPLICATIONSThe 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. AbbreviationsAng II, angiotensin II; AT1R, angiotensin II type 1 receptor; DHE, dihydroethidium; eNOS, endothelial NOS; HMG-CoA reductase, 3-hydroxy-3-methylglutaryl-coenzyme A reductase; L-NAME, N G -nitro-L-arginine methyl ester; RAAS, renin-angiotensin-aldosterone system; ROS, reactive oxygen species; SNP, sodium nitroprusside BJP British Journal of Pharmacology
This study examine whether consumption of cranberry juice could ameliorate endothelial dysfunction in estrogen deficiency. Vascular reactivity in aortas were studied in organ baths; protein levels of endothelial nitric oxide synthase (eNOS), phosphorylated eNOS, angiotensin converting enzyme (ACE), angiotensin II type 1 (AT1R) and type 2 receptors (AT2R), gp91phox and nitrotyrosine were detected by Western blot. Angiotensin II level was detected by immunohistochemical staining. Relaxations were impaired in OVX rats; which was prevented by AT1R blocker. Cranberry juice consumption ameliorated such endothelial dysfunction. Phenylephrine‐induced tension was higher in OVX rats, which was attenuated upon juice treatment. Our results showed cranberry juice consumption in OVX rats (i) increased p‐eNOS level; (ii) restored protein expressions of ACE, AT1R, gp91phox and nitrotyrosine; (iii) restored angiotensin II level in the aorta. These suggest chronic oral administration of cranberry juice during estrogen deficiency augments bioavailability of NO, due to a reduced level of AT1R‐mediated oxidative stress.
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