Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Ford, Rebecca J.; Rush, James W. E.

doi:10.1152/ajpheart.00597.2010

Cited by 43 publications

(70 citation statements)

References 59 publications

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“…Phosphatidyl-inositol-3-kinase (PI3K) and AMPK are 2 upstream modulators of NO release, which can act independently on their target. 19,20 We found that Compound C, an AMPK inhibitor, significantly blunted the vascular activity of resveratrol ( Figure 1C). In contrast, exposure to LY292002, a PI3K inhibitor, did not modify resveratrol-mediated vasorelaxation ( Figure 1C).…”

Section: Resveratrol Exerts a Vasorelaxant Effect By Modulating The Pmentioning

confidence: 88%

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

et al. 2013

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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...

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Section: Resveratrol Exerts a Vasorelaxant Effect By Modulating The Pmentioning

confidence: 88%

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

et al. 2013

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“…21 AMPK activation causes the NO-mediated relaxation in the spontaneously hypertensive rats. [25][26][27][28] AMPK, at the same time, causes the endothelium independent vascular smooth muscle relaxation in the aort preparations of the Mouse. 27 …”

Section: Adenosine Monophosphate-activated Protein Kinase Pathwaymentioning

confidence: 93%

“…23 Antidiabetic agents, such as, metformin 24 , thiazolidinediones, glukagon like peptid-1 agonists, dipeptidyl peptidase-4 inhibitors, statins, adiponectin and the leptin hormone increase the AMPK activation. 25,26 Experimentally, 5-aminoimidazole-4-carboxamide ribonucleoside is used for the AMPK activation 24 , whereas the dorsomorphine (compound C) is used for the inhibition.…”

Section: Adenosine Monophosphate-activated Protein Kinase Pathwaymentioning

confidence: 99%

“…It therefore shows a vasoprotective effect. [25][26][27] It is thought that the vasoprotective effects of the therapeutic agents like, metformin 24 , thiazolidinediones and statins also occur via the AMPK activation. 21 AMPK activation causes the NO-mediated relaxation in the spontaneously hypertensive rats.…”

Section: Adenosine Monophosphate-activated Protein Kinase Pathwaymentioning

confidence: 99%

“…On the other hand, it causes endothelium independent relaxation by decreasing intracellular Ca +2 sensitivity and vascular tonus through activating MLCK in vascular smooth muscle cell. [25][26][27] In summary, ROCK activation makes hypertension and diabetes like pathologies more critical by causing increase in vascular contraction. Increase in the AMPK activation, can help fixing vascular complications caused by these pathologies with its vasculoprotective effect.…”

Section: Rho-kinase and Adenosine Monophosphate-activated Protein Kinmentioning

confidence: 99%

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Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

Balcilar

Özakça

Altan

2017

tjps

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Vascular tonus is controlled by endothelium-derived relaxing factor (EDRF), endothelium-derived hyperpolarizing factor (EDHF) and endotheliumderived contracting factor (EDCF) under physiological circumstances. In pathological conditions, impairment of endothelium-derived relaxation can be caused by both decrease in EDRF release and increase in EDCF release. The increase in EDCF is observed with diseases such as hypertension and diabetes. The contribution of Rho-kinase and activated protein kinase (AMPK), which have opposite effects, to the increased EDCF responses was investigated. Rho-kinases are the effectors of Rho which is one of the small guanosine triphosphate-binding proteins. They increase cytosolic Ca +2 concentration and cause vascular smooth muscle to contract, keeping myosin light chain (MLC) in phosphorylated state by affecting myosin phosphatase target subunit which dephosphorylates the MLC. The activities of Rho-kinases increase with the increase of EDCF function. AMPK is the energy sensor of the cell. It provides a vasculoprotective effect by causing endothelium-dependent and endothelium-independent relaxation in smooth muscle. In contrast to Rho-kinase pathway activity, AMPK pathway activity decreases with diseases in which the EDCF function increases. In cases such as diabetes and hypertension that endothelial function impairs toward vasocontraction, it is considered that evaluating Rho-kinase and AMPK pathways which mediate contraction and relaxation in vascular smooth muscle respectively, would provide clues on choosing therapeutic target for pathologies in which endothelial dysfunction is observed. ÖZFizyolojik koşullarda vasküler tonus endotel kaynaklı rahatlatıcı faktörü (EDRF), endotel kaynaklı hiperpolarizasyon faktörü (EDHF) ve endotel kaynaklı kasılma faktörü (EDCF) tarafından kontrol edilmektedir. Patolojik durumlarda endotel kaynaklı gevşemenin azalması, EDRF üretimindeki azalmaya bağlı olabileceği gibi EDCF düzeyinin artmasına da bağlı olabilmektedir. EDCF hipertansiyon, diyabet gibi hastalıklarda artmaktadır. Diyabet, hipertansiyon gibi patolojik koşullarda artan EDCF yanıtına birbirine ters etki yapan Rho-kinaz ve aktive protein kinaz (AMPK) yolaklarının katkısı olabileceği düşünülmektedir. Rho-kinazlar küçük guanozin trifosfat-bağlı proteinlerden biri olan Rho'nun efektörüdür. Rho-kinazlar hafif zincir miyozini (MLC) defosforile eden miyozin fosfataz hedef altbirimine etki ederek MLC'nin fosforile halde kalmasının sağlayarak sitozolik Ca +2 konsantrasyonu artırır ve vasküler düz kasın kasılmasına neden olurlar. Rho-kinazların aktivitesi EDCF yanıtlarının arttığı hipertansiyon, kalp yetmezliği ve diyabet gibi hastalıklarda artmaktadır. AMPK ise hücrenin enerji sensörü olarak düşünülmektedir. Vasküler düz kasta endotel bağımlı ve bağımsız gevşemeyi sağlayarak vasküloprotektif etki sağlamaktadır. AMPK'nin aktivitesi Rho-kinaz yolağının aktivitesinin tersine EDCF fonksiyonunun arttığı hipertansiyon ve diyabet gibi hastalıklarda azalmaktadır. Endotel fonksiyonunun vazokonstriksiyon y...

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High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway

García‐Prieto

Hernández-Nuño

Rio

et al. 2014

Mol. Nutr. Food Res.

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Endothelium-dependent vasorelaxation to the AMPK activator AICAR is enhanced in aorta from hypertensive rats and is NO and EDCF dependent

Cited by 43 publications

References 59 publications

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

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

Contribution of Rho-kinase and Adenosine Monophosphate-Activated Protein Kinase Signaling Pathways to Endothelium-Derived Contracting Factors Responses

High-fat diet induces endothelial dysfunction through a down-regulation of the endothelial AMPK-PI3K-Akt-eNOS pathway

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