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

Abstract

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

Generation of Human Liver Chimeric Mice with Hepatocytes from Familial Hypercholesterolemia Induced Pluripotent Stem Cells

“…Alirocumab at 10 mg/kg/week improved EDV significantly in LRG mice engrafted with +/− (p < 0.01) or FH-1 iHeps (p < 0.05, Figures 5C and 5D), while there was no effect on LRG mice engrafted with −/− iHeps or vehicle (Figures 5E and 5F). In contrast, 10 mg/kg/day simvastatin improved EDV in aortas of all groups (Figures 5C–5F), supporting the knowledge that the vasoprotective effect of simvastatin is partially independent of LDLR status (Tian et al., 2011). Moderate synergistic effect of simvastatin and alirocumab on EDV in aortic rings was observed in LRG mice engrafted with +/− iHeps or FH-1 iHeps, but not −/− iHeps or vehicle (Figures 5C–5F).…”

Differential renal effects of candesartan at high and ultra-high doses in diabetic mice–potential role of the ACE2/AT2R/Mas axis

“…Previous reports demonstrated increased activation of MAPK in db/db [43,44], similar to our findings here. Candesartan variably attenuated activation of MAPKs, but at ultra-high doses, MAPK phosphorylation was amplified.…”

“…Unexpectedly, kidney cortex from db/db mice displayed decreased ACE activity and expression. This could explain why db/db mice have normal levels of blood pressure, despite the dramatic vascular endothelial dysfunction extensively described in type 2 diabetes [42,43]. Nevertheless, candesartan did not affect ACE activity or expression.…”

Luteolin Protects HUVECs from TNF-α-induced Oxidative Stress and Inflammation via its Effects on the Nox4/ROS-NF-κB and MAPK Pathways

“…For example, angiotensin-converting enzyme inhibitors, such as temocaprilat, or angiotensin Ⅱ receptor antagonists, such as olmesartan, not only inhibit the NADPH oxidase activity, including the p22phox expression, but also NF-κB activation, which induces the generation of ROS 41,42) . Statins also inhibit the NAPDH oxidase activity 43,44) and the activation of various related downstream signaling pathways, including that of p38 and ERK1/2, in order to produce anti-atherosclerotic effects 14,45) . Moreover, Fig.…”