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

García‐Prieto, Concha F.; Hernández-Nuño, Francisco; Rio, Danila Del; Ruiz‐Hurtado, Gema; Aránguez, Isabel; Ruiz‐Gayo, Mariano; Somoza, Beatriz; Fernández-Alfonso, Marı́a S.

doi:10.1002/mnfr.201400539

Cited by 64 publications

(65 citation statements)

References 50 publications

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“…AMPK activity is also reduced in ZDF [17] and in OLETF rats concurrently with a lower NO synthesis in aortic endothelium, thus correlating with endothelial dysfunction [15]. Similar results have been described for DIO models, where impaired endothelial function parallels with a down-regulation of AMPK and decreased NO availability [14,38]. In this scenario, we show in the current study that CR restores endothelial function in aorta of Zucker fa/fa rats through the up-regulation of AMPK activity and NO availability increase.…”

Section: Discussionsupporting

confidence: 73%

“…In cultured EC, both Akt [7] and PI3K [8] have been proposed as possible mediators of this action and the endothelial AMPK-PI3K-Akt-eNOS pathway has been demonstrated in whole vessels [14]. Moreover, it is known that CR promotes the activation of the AMPK-eNOS pathway that contributes to the revascularization in response to ischemia [27], to the improvement of vascular compliance [26], and to the reduction of blood pressure in hypertensive rats [26].…”

Section: Discussionmentioning

confidence: 98%

“…We have recently shown that an 8-week high-fat diet (HFD) reduces endothelial AMPK phosphorylation leading to a down-regulation of the PI3K-Akt-eNOS pathway that correlates with endothelial malfunction [14]. Decreased AMPK activity together with low rates of NO synthesis have been proposed to account for the impairment of endothelium-dependent relaxation in genetic models of obesity, such as the Otsuka Long Evans Tokushima Fatty (OLETF) rats [15] and young obese Zucker rats [16].…”

Section: Introductionmentioning

confidence: 99%

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Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats

García‐Prieto

Pulido-Olmo

Ruiz‐Hurtado

et al. 2015

Vascular Pharmacology

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Section: Discussionsupporting

confidence: 73%

Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

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Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats

García‐Prieto

Pulido-Olmo

Ruiz‐Hurtado

et al. 2015

Vascular Pharmacology

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“…On the other hand, patients with atherosclerosis, hypertension or type II diabetes mellitus suffer from hypercholesterolemia or dyslipidemia. This raises the question of whether high levels of plasma sEng might have an impact on the vascular wall only in the presence of another insult such as high cholesterol induced by an atherogenic diet [24], thereby contributing to the development of endothelial dysfunction in the conduit vessels in such conditions.…”

Section: Discussionmentioning

confidence: 99%

High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet

et al. 2016

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Aims: A soluble form of endoglin (sEng) was proposed to participate in the induction of endothelial dysfunction in small blood vessels. Here, we tested the hypothesis that high levels of sEng combined with a high-fat diet induce endothelial dysfunction in an atherosclerosis-prone aorta. Methods and Results: Six-month-old female and male transgenic mice overexpressing human sEng (Sol-Eng⁺) with low (Sol-Eng⁺low) or high (Sol-Eng⁺high) levels of plasma sEng were fed a high-fat rodent diet containing 1.25% cholesterol and 40% fat for 3 months. The plasma cholesterol and mouse sEng levels did not differ in the Sol-Eng⁺high and Sol-Eng⁺low mice. The expression of proinflammatory (P-selectin, ICAM-1, pNFκB and COX-2) and oxidative-stress-related markers (HO-1, NOX-1 and NOX-2) in the aortas of Sol-Eng⁺high female mice was significantly higher than in Sol-Eng⁺low female mice. Endothelium-dependent vasodilatation induced by acetylcholine was preserved better in the Sol-Eng⁺high female mice than in the Sol-Eng⁺low female mice. Conclusion: These results suggest that high concentrations of sEng in plasma in combination with a high-fat diet induce the simultaneous activation of proinflammatory, pro-oxidative and vasoprotective mechanisms in mice aorta and the balance of these biological processes determines whether the final endothelial phenotype is adaptive or maladaptive.

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“…For example, high-fat diet (HFD) induces a downregulation of the endothelial AMPK-PI3K-Akt-eNOS pathway which in turn causes ED; such downregulation of the AMPK-PI3K-Akt-eNOS pathway correlates with increased plasma levels of FFAs and TG, and an impaired glucose utilization [44]. Besides, uric acid (UA), which is a final product derived from purine metabolism pathway, can induce ED via the high mobility group box chromosomal protein 1/receptor for advanced glycation end products (HMGB1/RAGE axis).…”

Section: Biology Of the Endothelium And Endothelial Dysfunctionmentioning

confidence: 99%

Role of free fatty acids in endothelial dysfunction

et al. 2017

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Plasma free fatty acids levels are increased in subjects with obesity and type 2 diabetes, playing detrimental roles in the pathogenesis of atherosclerosis and cardiovascular diseases. Increasing evidence showing that dysfunction of the vascular endothelium, the inner lining of the blood vessels, is the key player in the pathogenesis of atherosclerosis. In this review, we aimed to summarize the roles and the underlying mechanisms using the evidence collected from clinical and experimental studies about free fatty acid-mediated endothelial dysfunction. Because of the multifaceted roles of plasma free fatty acids in mediating endothelial dysfunction, elevated free fatty acid level is now considered as an important link in the onset of endothelial dysfunction due to metabolic syndromes such as diabetes and obesity. Free fatty acid-mediated endothelial dysfunction involves several mechanisms including impaired insulin signaling and nitric oxide production, oxidative stress, inflammation and the activation of the renin-angiotensin system and apoptosis in the endothelial cells. Therefore, targeting the signaling pathways involved in free fatty acid-induced endothelial dysfunction could serve as a preventive approach to protect against the occurrence of endothelial dysfunction and the subsequent complications such as atherosclerosis.

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

Abstract: Endothelial dysfunction caused by HFD is related to a dysfunctional endothelial AMPK-PI3K-Akt-eNOS pathway correlating with the increase of plasma NEFA, TG, and an impaired glucose management.

Cited by 64 publications

References 50 publications

Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats

Mild caloric restriction reduces blood pressure and activates endothelial AMPK-PI3K-Akt-eNOS pathway in obese Zucker rats

High Levels of Soluble Endoglin Induce a Proinflammatory and Oxidative-Stress Phenotype Associated with Preserved NO-Dependent Vasodilatation in Aortas from Mice Fed a High-Fat Diet

Role of free fatty acids in endothelial dysfunction

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