Rapamycin inhibits hydrogen peroxide-induced loss of vascular contractility

Gao, Ge; Li, Jingjing; Li, Yuenan; Liu, Dong; Wang, Yuebing; Wang, Lifeng; Tang, Xiang D.; Walsh, Michael P.; Gui, Yu; Zheng, Xi-Long

doi:10.1152/ajpheart.01084.2010

Cited by 20 publications

(13 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…HIF‐2α expression is controlled by mTOR complex 2 (mTORC2) rather than mTORC1 (Toschi et al ., ). It is assumed that mTORC2 is less sensitive to rapamycin than mTORC1 but the high concentration of rapamycin (20 μM) used in our study has been demonstrated to block mTORC2 signalling in vascular tissue (Gao et al ., ). Thus, the lack of inhibition by rapamycin of FM19G11‐induced improvement of endothelial vasodilatation in IRR suggests that any effects of FM19G11 on either HIF‐1α or HIF‐2α expression do not contribute to its ability to restore endothelial function.…”

Section: Discussionmentioning

confidence: 97%

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

Assar

Sánchez-Puelles

Royo

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

BACKGROUND AND PURPOSEFM19G11 up-regulates mammalian target of rapamycin (mTOR)/hypoxia inducible factor-1α (HIF-1α) and PI3K/Akt pathways, which are involved in endothelial function. We evaluated the effects of FM19G11 on defective endothelial vasodilatation in arteries from rats and humans and investigated the mechanisms involved. EXPERIMENTAL APPROACHEffects of chronic in vivo administration of FM19G11 on aortic endothelial vasodilatation were evaluated together with ex vivo treatment in aortic and mesenteric arteries from control and insulin-resistant rats (IRR). Its effects on vasodilator responses of penile arteries (HPRAs) and corpus cavernosum (HCC) from men with vasculogenic erectile dysfunction (ED) (model of human endothelial dysfunction) were also evaluated. Vascular expression of phosphorylated-endothelial NOS (p-eNOS), phosphorylated-Akt (p-Akt) and HIF-1α was determined by immunodetection and cGMP by ELISA. KEY RESULTSChronic administration of FM19G11 reversed the impaired endothelial vasodilatation in IRR. Ex vivo treatment with FM19G11 also significantly improved endothelium-dependent vasodilatation in aorta and mesenteric arteries from IRR. These effects were accompanied by the restoration of p-eNOS and cGMP levels in IRR aorta and were prevented by either NOS or PI3K inhibition. p-Akt and p-eNOS contents were increased by FM19G11 in aortic endothelium of IRR. FM19G11-induced restoration of endothelial vasodilatation was unaffected by mTOR/HIF-1α inhibitors. FM19G11 also restored endothelial vasodilatation in HPRA and HCC from ED patients. CONCLUSIONS AND IMPLICATIONSStimulation of the PI3K/Akt/eNOS pathway by FM19G11 alleviates impaired NO-mediated endothelial vasodilatation in rat and human arteries independently of mTOR/HIF-1α activation. This pharmacological strategy could be beneficial for managing pathological conditions associated with endothelial dysfunction, such as ED. AbbreviationsCR, control rats; ED, erectile dysfunction; eNOS, endothelial NOS; HCC, human corpus cavernosum; HIF-1α, hypoxia inducible factor-1α; HPRA, human penile resistance arteries; IRR, insulin-resistant rats; L-NAME, N G -nitro-L-arginine methyl ester; mTOR, mammalian target of rapamycin; p-eNOS, phosphorylated eNOS; p-Akt, phosphorylated-Akt; SNP, sodium nitroprusside IntroductionEndothelial dysfunction is a key process in the pathogenesis of cardiovascular disease. It precedes the disease's clinical manifestations and predicts future cardiovascular events (Green et al., 2011). Situations increasing the risk of cardiovascular disease, such as diabetes, hypertension and ageing, are clearly associated with the presence of endothelial dysfunction. Therapeutic strategies targeted at preserving or restoring endothelial function are key to the prevention of cardiovascular disease. NO participates in many functions of the endothelium and is a key mediator of endotheliumdependent vasodilatation. In fact, the main risk factors for cardiovascular disease in humans all share the characteristic of defective NO-mediated vas...

show abstract

Section: Discussionmentioning

confidence: 97%

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

Assar

Sánchez-Puelles

Royo

et al. 2015

British J Pharmacology

View full text Add to dashboard Cite

show abstract

“…Earlier studies demonstrated the antioxidant effect of Rapamycin by protecting mitochondria against oxidative stress and apoptosis in a rat model of Parkinson disease [69], by improving endothelial function in aging [70] and vascular contractility [71]. Rapamycin also protects human corneal endothelial cells from oxidative injury-mediated cell death via inhibition of ROS production [72].…”

Section: Discussionmentioning

confidence: 99%

Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

Filippone

Samidurai

Roh

et al. 2017

Oxidative Medicine and Cellular Longevity

View full text Add to dashboard Cite

Prompt coronary reperfusion is the gold standard for minimizing injury following acute myocardial infarction. Rapamycin, mammalian target of Rapamycin (mTOR) inhibitor, exerts preconditioning-like cardioprotective effects against ischemia/reperfusion (I/R) injury. We hypothesized that Rapamycin, given at the onset of reperfusion, reduces myocardial infarct size through modulation of mTOR complexes. Adult C57 male mice were subjected to 30 min of myocardial ischemia followed by reperfusion for 1 hour/24 hours. Rapamycin (0.25 mg/kg) or DMSO (7.5%) was injected intracardially at the onset of reperfusion. Post-I/R survival (87%) and cardiac function (fractional shortening, FS: 28.63 ± 3.01%) were improved in Rapamycin-treated mice compared to DMSO (survival: 63%, FS: 17.4 ± 2.6%). Rapamycin caused significant reduction in myocardial infarct size (IS: 26.2 ± 2.2%) and apoptosis (2.87 ± 0.64%) as compared to DMSO-treated mice (IS: 47.0 ± 2.3%; apoptosis: 7.39 ± 0.81%). Rapamycin induced phosphorylation of AKT S473 (target of mTORC2) but abolished ribosomal protein S6 phosphorylation (target of mTORC1) after I/R. Rapamycin induced phosphorylation of ERK1/2 but inhibited p38 phosphorylation. Infarct-limiting effect of Rapamycin was abolished with ERK inhibitor, PD98059. Rapamycin also attenuated Bax and increased Bcl-2/Bax ratio. These results suggest that reperfusion therapy with Rapamycin protects the heart against I/R injury by selective activation of mTORC2 and ERK with concurrent inhibition of mTORC1 and p38.

show abstract

“…In line with the above findings, Cd-induced reactive oxygen species (ROS) also down-regulates the protein expression of PTEN and the activity of PP2A in PC12 cells, SH-SY5Y cells and primary neurons [ 20 , 36 ]. Of note, growing evidence has shown that rapamycin has the ability to attenuate oxidative stress-induced cell damage or death [ 12 , 20 , 58 , 59 ]. For example, rapamycin inhibits H 2 O 2 -induced loss of vascular contractility [ 59 ].…”

Section: Discussionmentioning

confidence: 99%

Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium

Zhang

Liu

et al. 2015

Oncotarget

View full text Add to dashboard Cite

Cadmium (Cd), an environmental contaminant, causes neurodegenerative disorders. Recently we have shown that rapamycin prevents Cd-induced neuronal cell death by inhibiting mTOR signaling pathway. Here we found that rapamycin exerted its prevention against Cd-induced neuronal cell death also partially via blocking Erk1/2 pathway. Inhibiting Erk1/2 with PD98059 or silencing Erk1/2 potentiated rapamycin's inhibition of Cd-induced phosphorylation of Erk1/2 and apoptosis in neuronal cells. Both PP2A and PTEN/Akt were involved in the regulation of Erk1/2 activation and cell death triggered by Cd. Inhibition of PP2A with okadaic acid or ectopic expression of dominant negative PP2A attenuated rapamycin's inhibition of Cd-induced phospho-Erk1/2 and apoptosis, whereas over-expression of wild-type PP2A enhanced rapamycin's effects; Over-expression of wild-type PTEN or dominant negative Akt, or inhibition of Akt with Akt inhibitor X strengthened rapamycin's inhibition of Cd-induced phospho-Erk1/2 and cell death. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T) blocked rapamycin's inhibitory effects on Cd-induced inhibition of PP2A, down-regulation of PTEN, and activation of Akt, leading to Erk1/2 activation and cell death, whereas silencing mTOR mimicked rapamycin's effects. The results uncover that rapamycin inhibits Cd activation of Erk1/2-mediated neuronal apoptosis through intervening mTOR-PP2A/PTEN signaling network.

show abstract

Rapamycin inhibits hydrogen peroxide-induced loss of vascular contractility

Cited by 20 publications

References 49 publications

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

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

Reperfusion Therapy with Rapamycin Attenuates Myocardial Infarction through Activation of AKT and ERK

Rapamycin inhibits Erk1/2-mediated neuronal apoptosis caused by cadmium

Contact Info

Product

Resources

About