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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 (AT?R), 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 AT?R, 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 AT?R-NAD(P)H oxidase cascade.

SUBMITTER: Tian XY

PROVIDER: S-EPMC3188899 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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

Tian X Y XY Wong W T WT Xu A A Chen Z Y ZY Lu Y Y Liu L M LM Lee V W VW Lau C W CW Yao X X Huang Y Y

British journal of pharmacology 20110901 2b

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>Twelve-week-old db/db diabetic mice were treated w ...[more]

PMID: 21486274

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Project description:Oxidative stress plays an important role in type 2 diabetes-related endothelial dysfunction. We hypothesized that resveratrol protects against oxidative stress-induced endothelial dysfunction in aortas of diabetic mice by inhibiting tumor necrosis factor alpha (TNFalpha)-induced activation of NAD(P)H oxidase and preserving phosphorylation of endothelial nitric oxide synthase (eNOS).We examined endothelial-dependent vasorelaxation to acetylcholine (ACh) in diabetic mice (Lepr(db)) and normal controls (m Lepr(db)). Relaxation to ACh was blunted in Lepr(db) compared with m Lepr(db), whereas endothelial-independent vasorelaxation to sodium nitroprusside (SNP) was comparable. Resveratrol improved ACh-induced vasorelaxation in Lepr(db) without affecting dilator response to SNP. Impaired relaxation to ACh in Lepr(db) was partially reversed by incubating the vessels with NAD(P)H oxidase inhibitor apocynin and a membrane-permeable superoxide dismutase mimetic TEMPOL. Dihydroethidium (DHE) staining showed an elevated superoxide (O(2)(.-)) production in Lepr(db), whereas both resveratrol and apocynin significantly reduced O(2)(.-) signal. Resveratrol increased nitrite/nitrate levels and eNOS (Ser1177) phosphorylation, and attenuated H(2)O(2) production and nitrotyrosine (N-Tyr) content in Lepr(db) aortas. Furthermore, resveratrol attenuated the mRNA and protein expression of TNFalpha. Genetic deletion of TNFalpha in diabetic mice (db(TNF-)/db(TNF-)) was associated with a reduced NAD(P)H oxidase activity and vascular O(2)(.-) production and an increased eNOS (Ser1177) phosphorylation, suggesting that TNFalpha plays a pivotal role in aortic dysfunction in diabetes by inducing oxidative stress and reducing NO bioavailability.Resveratrol restored endothelial function in type 2 diabetes by inhibiting TNFalpha-induced activation of NAD(P)H oxidase and preserving eNOS phosphorylation, suggesting the potential for new treatment approaches to promote vascular health in metabolic diseases.

Project description:Diminished release and function of endothelium-derived nitric oxide coupled with increases in reactive oxygen species production is critical in endothelial dysfunction. Recent evidences have shown that activation of the protective axis of the renin-angiotensin system composed by angiotensin-converting enzyme 2, angiotensin-(1-7), and Mas receptor promotes many beneficial vascular effects. This has led us to postulate that activation of intrinsic angiotensin-converting enzyme 2 would improve endothelial function by decreasing the reactive oxygen species production. In the present study, we tested 1-[[2-(dimetilamino)etil]amino]-4-(hidroximetil)-7-[[(4-metilfenil)sulfonil]oxi]-9H-xantona-9 (XNT), a small molecule angiotensin-converting enzyme 2 activator, on endothelial function to validate this hypothesis. In vivo treatment with XNT (1 mg/kg per day for 4 weeks) improved the endothelial function of spontaneously hypertensive rats and of streptozotocin-induced diabetic rats when evaluated through the vasorelaxant responses to acetylcholine/sodium nitroprusside. Acute in vitro incubation with XNT caused endothelial-dependent vasorelaxation in aortic rings of rats. This vasorelaxation effect was attenuated by the Mas antagonist D-pro7-Ang-(1-7), and it was reduced in Mas knockout mice. These effects were associated with reduction in reactive oxygen species production. In addition, Ang II-induced reactive oxygen species production in human aortic endothelial cells was attenuated by preincubation with XNT. These results showed that chronic XNT administration improves the endothelial function of hypertensive and diabetic rat vessels by attenuation of the oxidative stress. Moreover, XNT elicits an endothelial-dependent vasorelaxation response, which was mediated by Mas. Thus, this study indicated that angiotensin-converting enzyme 2 activation promotes beneficial effects on the endothelial function and it is a potential target for treating cardiovascular disease.

Project description:AimsAngiotensin II (AngII)-induced superoxide (O2(•-)) production by the NADPH oxidases and mitochondria has been implicated in the pathogenesis of endothelial dysfunction and hypertension. In this work, we investigated the specific molecular mechanisms responsible for the stimulation of mitochondrial O2(•-) and its downstream targets using cultured human aortic endothelial cells and a mouse model of AngII-induced hypertension.ResultsWestern blot analysis showed that Nox2 and Nox4 were present in the cytoplasm but not in the mitochondria. Depletion of Nox2, but not Nox1, Nox4, or Nox5, using siRNA inhibits AngII-induced O2(•-) production in both mitochondria and cytoplasm. Nox2 depletion in gp91phox knockout mice inhibited AngII-induced cellular and mitochondrial O2(•-) and attenuated hypertension. Inhibition of mitochondrial reverse electron transfer with malonate, malate, or rotenone attenuated AngII-induced cytoplasmic and mitochondrial O2(•-) production. Inhibition of the mitochondrial ATP-sensitive potassium channel (mitoK(+)ATP) with 5-hydroxydecanoic acid or specific PKCɛ peptide antagonist (EAVSLKPT) reduced AngII-induced H2O2 in isolated mitochondria and diminished cytoplasmic O2(•-). The mitoK(+)ATP agonist diazoxide increased mitochondrial O2(•-), cytoplasmic c-Src phosphorylation and cytoplasmic O2(•-) suggesting feed-forward regulation of cellular O2(•-) by mitochondrial reactive oxygen species (ROS). Treatment of AngII-infused mice with malate reduced blood pressure and enhanced the antihypertensive effect of mitoTEMPO. Mitochondria-targeted H2O2 scavenger mitoEbselen attenuated redox-dependent c-Src and inhibited AngII-induced cellular O2(•-), diminished aortic H2O2, and reduced blood pressure in hypertensive mice.Innovation and conclusionsThese studies show that Nox2 stimulates mitochondrial ROS by activating reverse electron transfer and both mitochondrial O2(•-) and reverse electron transfer may represent new pharmacological targets for the treatment of hypertension.

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

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

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