Reversal of Endothelial Nitric Oxide Synthase Uncoupling and Up-Regulation of Endothelial Nitric Oxide Synthase Expression Lowers Blood Pressure in Hypertensive Rats

Li, Huige; Witte, Klaus; August, Michael; Brausch, Isolde; Gödtel-Armbrust, Ute; Habermeier, Alice; Closs, Ellen I.; Oelze, Mathias; Münzel, Thomas; Förstermann, Ulrich

doi:10.1016/j.jacc.2006.01.071

Cited by 166 publications

(118 citation statements)

References 40 publications

Supporting

Mentioning

108

Contrasting

Unclassified

Order By: Relevance

“…Clofibrate-mediated improvement in vasoconstriction and accompanying increase in NO confirms the hypothesis that clofibrate-mediated reduction in blood pressure involves NO. At the same time reduced ROS generation in SHR by clofibrate agrees with earlier studies showing an increased ROS generation and NAD(P)H oxidase activity in SHR rats where eNOS "uncoupling" in hypertension was proposed [27] . At the same time, reduced vasoconstriction response to endogenous vasoconstrictor in SHR by clofibrate propose that clofibrate-mediated induction of PPARα may have a role on PE, AII, TxA 2 and ET-1.…”

Section: Discussionsupporting

confidence: 91%

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Yousefipour

Newaz

2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

Aim: Peroxisome proliferator activated receptors (PPARs) are nuclear transcription factors that regulate numerous genes influencing blood pressure. The aim of this study was to examine the effects of clofibrate, a PPARα ligand, on blood pressure in spontaneously hypertensive rats (SHR). Methods: Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), 8-9 weeks old, were randomly allocated into groups treated with vehicle or clofibrate (250 mg·kg -1 ·d -1 , ip for 21 d). Systolic blood pressure (SBP) was measured before and after the study period using tail-cuff plethysmography. Rats were sacrificed under anesthesia and blood, urine and tissue samples were processed for subsequent analysis. Results: SHR rats showed significantly higher SBP compared with WKY rats (198±6 mmHg vs 93±7 mmHg), and a 3-fold increase in urinary protein excretion. Clofibrate treatment reduced SBP by 26%±2% and proteinuria by 43%±9% in SHR but not in WKY rats. The urinary nitrite/nitrate excretion in SHR rats was nearly 2-fold greater than that in WKY, and was further increased by 30%±4% and 48%±3%, respectively, following clofibrate treatment. In addition, PPARα protein expression and PPARα activity were significantly lower in SHR than that in WKY rats. Clofibrate treatment significantly increased PPARα protein expression and PPARα activity in SHR rats, but not in WKY rats. Moreover, the vasoconstrictor response of aortic ring was markedly increased in SHRs, which was blunted after clofibrate treatment. Conclusion: PPARα contributes to regulation of blood pressure and vascular reactivity in SHR, and clofibrate-mediated reduction in blood pressure and proteinuria is probably through increased NO production.

show abstract

Section: Discussionsupporting

confidence: 91%

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Yousefipour

Newaz

2014

Acta Pharmacol Sin

View full text Add to dashboard Cite

show abstract

“…It should be noted that NO is the primary regulator of vascular function, because it induces vasodilatation, inhibits platelet adhesion and aggregation, and reduces leukocyte-endothelial cell interaction. [5][6][7] This could explain the critical role of NO in IPC-induced endothelial protection.…”

Section: Discussionmentioning

confidence: 96%

“…[1][2][3][4] Moreover, the arterial endothelial nitric oxide synthase (eNOS) protein expression is severely reduced after I/R injury. 3 Given the well-known role of nitric oxide (NO) not only as a vasodilator but also as an inhibitor of neutrophil adhesion and platelet aggregation, [5][6][7] the amelioration of the endothelial dysfunction associated with I/R through the maintenance of an adequate level of eNOS could be important. Reactive oxygen/nitrogen species (ROS/RNS) generation on reperfusion is also generally accepted as a contributing factor to I/R-induced vascular injury.…”

mentioning

confidence: 99%

Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS

Zhao

et al. 2013

Laboratory Investigation

View full text Add to dashboard Cite

Ischemic preconditioning (IPC) strongly protects against ischemia/reperfusion (I/R) injury; however, the molecular mechanism involved in delayed preconditioning-induced endothelial protection in peripheral arteries is unknown. Therefore, we examined using functional, morphologic and molecular biologic studies whether delayed IPC decreases formation of reactive oxygen species and upregulates endothelial nitric oxide synthase (eNOS) that in turn contributes to vascular endothelial protection. Adult male Sprague-Dawley rats were subjected to 30-min ischemia induced by mesenteric artery occlusion followed by 60-min reperfusion 24 h after sham surgery or preconditioning (three cycles of 5-min ischemia/5-min reperfusion). Delayed preconditioning prevented the I/R-induced impairment of endothelium-dependent relaxations to acetylcholine (maximal relaxation: sham 91.4 ± 2.2%; I/R 54.0 ± 4.0%; IPC 80.2 ± 6.3%). This protective effect was abolished by NOS inhibitor N G -nitro-L-arginine methyl ester and not changed by ascorbic acid. Electron microscopy showed marked endothelial damage after I/R and the ultrastructural changes were prevented by delayed preconditioning. Following I/R, the impairment of eNOS phosphorylation and expression was observed in mesenteric vessels. Furthermore, phosphatidylinositol 3-kinase (PI3K) and Akt phosphorylation were reduced, although total PI3K and Akt remained unchanged. IPC restored I/R-induced impairment of eNOS expression and activity. This was possibly the result of the recovery of PI3K/Akt phosphorylation. Furthermore, I/R increased serum level of malondialdehyde, intravascular superoxide and nitrotyrosine generation, which were abrogated by IPC. These results suggest that delayed preconditioning prevented I/R-induced endothelial injury in peripheral resistance vasculature, both in terms of functional and structural changes. Endothelial protection afforded by delayed IPC is associated with inhibition of oxidative stress and upregulation of PI3K/Akt/eNOS pathway.

show abstract

“…37 Cardiovascular risk factors, such as diabetes mellitus, hypertension, hypercholesterolemia, and cigarette smoke, reduce bioactive NO. 38,39 These risk factors lead to an enhanced production of reactive oxygen species in vessel walls. BH 4 is highly sensitive to oxidation and, with BH 4 deficiency, oxygen reduction uncouples from NO synthesis, thereby converting eNOS into a superoxide-producing enzyme.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

et al. 2013

View full text Add to dashboard Cite

Abstract-Epidemiological studies have demonstrated that the Mediterranean diet, which is rich in resveratrol, is associated with a significantly reduced risk of cardiovascular disease. However, the molecular mechanisms that underlie the beneficial effects of resveratrol on cardiovascular function remain incompletely understood. Therefore, we set out to identify the molecular target(s) mediating the protective action of resveratrol on vascular function. To this end, we performed vascular reactivity studies to evaluate the effects of resveratrol on superior thyroid artery obtained from 59 patients with hypertension and dyslipidemia. We found that resveratrol evoked vasorelaxation and reduced endothelial dysfunction through the modulation of NO metabolism via (1) an 5′ adenosine monophosphate-activated protein kinase-mediated increase in endothelial NO synthase activity; (2) a rise in tetrahydrobiopterin levels, which also increases endothelial NO synthase activity; and (3) attenuation of vascular oxidative stress, brought about by overexpression of manganese superoxide dismutase via an nuclear factor erythroid-derived 2-like 2-dependent mechanism. The effects of resveratrol on acetylcholine vasorelaxation were also tested in vessels from patients with nonhypertensive nondyslipidemia undergoing thyroid surgery. In this setting, resveratrol failed to exert any effect. Thus, our finding that resveratrol reduces endothelial dysfunction, an early pathophysiological feature and independent predictor of poor prognosis in most forms of cardiovascular disease, supports the concept that the risk of vascular events could be further reduced by adherence to a set of dietary and behavioral guidelines. MethodsFor detailed methodology, please see the online-only Data Supplement. In brief, we collected superior thyroid artery (STA) from patients with HD (Table). Each vessel was divided into rings for use in different experimental series. Some rings were treated with resveratrol at 37°C, and then proteins were rapidly extracted for molecular studies to evaluate total and phosphorylated endothelial NO synthase (eNOS) protein levels, eNOS dimerization, GTP cyclohydrolase 1, copper-zinc superoxide dismutase (Cu-ZnSOD) and MnSOD expression, and NRF2 translocation; other rings were kept in 4°C Krebs solution for vascular reactivity studies; some were used for highperformance liquid chromatography (HPLC) dosage of BH 4 ; and others were rapidly used for measurement of O 2 − . Studies were also performed on vessels removed from patients with nonhypertensive, nondyslipidemia (nHD) undergoing thyroid surgery. Results Resveratrol Exerts a Vasorelaxant Effect by Modulating the Phosphorylation Status of eNOS and NO ReleaseEvaluation of the vascular reactivity of ex vivo STA from patients with HD revealed that endothelially mediated (acetylcholine-evoked) vasorelaxation was significantly blunted compared with relaxation induced by nitroglycerin ( Figure 1A). However, when HD STA rings were preconstricted with phenylephrine, resveratrol was ca...

show abstract

Reversal of Endothelial Nitric Oxide Synthase Uncoupling and Up-Regulation of Endothelial Nitric Oxide Synthase Expression Lowers Blood Pressure in Hypertensive Rats

Abstract: Pharmacologic interventions that combine eNOS up-regulation and reversal of eNOS uncoupling can markedly increase bioactive NO in the vasculature and produce beneficial hemodynamic effects such as a reduction of blood pressure.

Cited by 166 publications

References 40 publications

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

PPARα ligand clofibrate ameliorates blood pressure and vascular reactivity in spontaneously hypertensive rats

Delayed preconditioning prevents ischemia/reperfusion-induced endothelial injury in rats: role of ROS and eNOS

Resveratrol Improves Vascular Function in Patients With Hypertension and Dyslipidemia by Modulating NO Metabolism

Contact Info

Product

Resources

About