<scp>FM</scp>19<scp>G</scp>11 reverses endothelial dysfunction in rat and human arteries through stimulation of the <scp>PI3K/Akt/eNOS</scp> pathway, independently of <scp>mTOR</scp>/<scp>HIF</scp>‐1α activation

Assar, Mariam El; Sánchez-Puelles, José María; Royo, Inmaculada; López-Hernández, Eva; Sánchez-Ferrer, Alberto; Aceña, José Luis; Rodríguez‐Mañas, Leocadio; Angulo, Javier

doi:10.1111/bph.12993

Cited by 24 publications

(25 citation statements)

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“…Additionally, HHCy is a recognized risk factor for endothelial dysfunction and related disorders, including CVD and ED2021. NO, the key mediator synthesized by different NO synthase isoenzymes (eNOS, nNOS, and inducible NOS), plays an essential role in endothelial function222324. Sexual stimuli induce an increase in serum levels of testosterone and the release of NO from penile nerve endings and endothelial cells, which in turn relax cavernous smooth muscle and increase blood flow to the penis25.…”

Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity

Jiang

Xiong

Yang

et al. 2016

Sci Rep

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To investigate the effect of hyperhomocysteinaemia (HHCy) on penile erectile function in a rat model, a methionine-rich diet was used in which erectile function, the reproductive system, and nitric oxide synthase were characterized. The intracavernous pressure, apomorphine experiments, measurement of oxidative stress, hematoxylin and eosin staining, immunohistochemistry analysis, reverse transcription-polymerase chain reactions and measurement of endothelial nitric oxide synthase activity were utilized. Our results showed that erections in the middle-dose, high-dose, and interference (INF) groups were significantly lower than the control (P < 0.05). INF group, being fed with vitamins B and folic acid, demonstrated markedly improved penile erections compared with the middle-dose group (P < 0.05). HHCy-induced eNOS and phospho-eNOS protein expression was reduced and the antioxidant effect was markedly impaired. The data of the present data provide evidence that HHCy is a vascular risk factor for erectile dysfunction by impairing cavernosa endothelial nitric oxide synthase activity. Intake of vitamins B can alleviate this abnormality.

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Section: Discussionmentioning

confidence: 99%

Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity

Jiang

Xiong

Yang

et al. 2016

Sci Rep

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“…siRNA sestrin2 (300 pmol/1μl, mixed by three different rat-derived siRNA with siRNA ID: SASI_Rn02_00247651, SASI_Rn02_00247652, SASI_Rn02_00247645, Sigma-Aldrich, USA), and scramble RNA (300 pmol/1μl) were delivered by intracerebroventricular injection, 2μl drug per pup injected slowly in 5min (Chen et al, 2015), at 1.5 mm posterior, 1.5mm lateral to the bregma and 1.7mm deep on the ipsilateral hemisphere at 24h pre HI. DMOG (HIF1α activator) (40 mg/kg, Sigma-Aldrich, USA)(Nagel et al, 2011) and FM19G11 (HIF1α inhibitor) (10 mg/kg, Sigma-Aldrich, USA) (El Assar et al, 2015) were injected intraperitoneally at 60min, and 30min after HI respectively (Lekic et al, 2015). …”

Section: Methodsmentioning

confidence: 99%

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Shi

Doycheva

et al. 2016

Neurobiology of Disease

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Objective Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injury. Methods Rat pups underwent common carotid artery ligation followed by either 150 min (severe model) or 100 min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) were used to examine their roles on BBB permeability. Results Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. Conclusions rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α’s effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.

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“… b ; El Assar et al . c ). Four‐ to 5‐week‐old rats were fed with fructose (20% w/v) in drinking water for 8 weeks.…”

Section: Methodsmentioning

confidence: 99%

Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans

Assar

Angulo

Santos-Ruiz³

et al. 2016

The Journal of Physiology

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Key pointsr The presence of insulin resistance (IR) is determinant for endothelial dysfunction associated with obesity.r Although recent studies have implicated the involvement of mitochondrial superoxide and inflammation in the defective nitric oxide (NO)-mediated responses and subsequent endothelial dysfunction in IR, other mechanisms could compromise this pathway.r In the present study, we assessed the role of asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of endothelium-dependent vasodilatation in human morbid obesity and in a non-obese rat model of IR.r We show that both increased ADMA and up-regulated arginase are determinant factors in the alteration of the L-arginine/NO pathway associated with IR in both models and also that acute treatment of arteries with arginase inhibitor or with L-arginine significantly alleviate endothelial dysfunction.r These results help to expand our knowledge regarding the mechanisms of endothelial dysfunction that are related to obesity and IR and establish potential therapeutic targets for intervention.Abstract Insulin resistance (IR) is determinant for endothelial dysfunction in human obesity. Although we have previously reported the involvement of mitochondrial superoxide and inflammation, other mechanisms could compromise NO-mediated responses in IR. We evaluated the role of the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) and arginase with respect to IR-induced impairment of L-arginine/NO-mediated vasodilatation in human morbid obesity and in a non-obese rat model of IR. Bradykinin-induced vasodilatation was evaluated in microarteries derived from insulin-resistant morbidly obese (IR-MO) and non-insulin-resistant MO (NIR-MO) subjects. Defective endothelial vasodilatation in IR-MO was improved by L-arginine supplementation. Increased levels of ADMA were detected in serum and adipose tissue from IR-MO. Serum ADMA positively correlated with IR score and negatively with pD 2 for bradykinin. Gene expression determination by RT-PCR revealed not only the decreased expression of ADMA degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH)1/2 in IR-MO microarteries, but also increased expression of arginase-2. non-obese IR model (fructose-fed rat) confirmed an elevation of circulating and aortic ADMA concentrations, as well as reduced DDAH aortic content and increased aortic arginase activity in IR. Improvement of endothelial vasodilatation in IR rats by L-arginine supplementation and arginase inhibition provided functional corroboration. These results demonstrate that increased ADMA and up-regulated arginase contribute to endothelial dysfunction as determined by the presence of IR in human obesity, most probably by compromising arginine availability. The results provide novel insights regarding the mechanisms of endothelial dysfunction related to obesity and IR and establish potential therapeutic targets for intervention.

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FM19G11 reverses endothelial dysfunction in rat and human arteries through stimulation of the PI3K/Akt/eNOS pathway, independently of mTOR/HIF‐1α activation

Cited by 24 publications

References 53 publications

Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity

Hyperhomocysteinaemia in rats is associated with erectile dysfunction by impairing endothelial nitric oxide synthase activity

Sestrin2 induced by hypoxia inducible factor1 alpha protects the blood-brain barrier via inhibiting VEGF after severe hypoxic-ischemic injury in neonatal rats

Asymmetric dimethylarginine (ADMA) elevation and arginase up‐regulation contribute to endothelial dysfunction related to insulin resistance in rats and morbidly obese humans

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