Inhibitory effect of 14,15-EET on endothelial senescence through activation of mTOR complex 2/Akt signaling pathways

Yang, Cui; Pan, Shitian; Yan, Saimei; Li, Zhuoming; Yang, Jinyan; Wang, Ying; Xiong, Yong

doi:10.1016/j.biocel.2014.02.020

Cited by 17 publications

(11 citation statements)

References 24 publications

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“…We also demonstrate that mitigation of radiation renal injury by captopril or EET-A is associated with reduced kidney mRNA expression of p53 as well as the mRNA expressions of Fas, FasL and caspase 8. In several in vitro studies, ACEi and EET have been shown to decrease Fas and p53 expression and exert anti-apoptotic effects [63,64]. Overall, our findings support the notion that in radiation renal injury renal apoptosis occurs by the Fas/FasL arm of extrinsic apoptotic pathway, and this was mitigated by captopril or EET-A.…”

Section: Discussionsupporting

confidence: 88%

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

et al. 2016

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Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP-epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analog, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared to non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared to control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen compared to control, and EET-A or captopril decreased BUN by 40–60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60–90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50–90%. Renal interstitial fibrosis, tubular, and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which EET-A or captopril mitigated. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on p53/Fas/FasL apoptotic pathway. Overall, this study demonstrates a novel EET-analog based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

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Section: Discussionsupporting

confidence: 88%

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

et al. 2016

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“…al. showed that the endothelial function was gradually reduced in 6-week, 20-week, and 80-week Sprague-Dawley rats and addition of exogenous cis- 14,15-EET improved endothelial function in aging mice as well as endothelial senescence in rat mesenteric arterial endothelial cells from 20-week-old rat through mTORC2/Akt signaling pathway [33]. 11,12-EET also attenuated inflammation by reducing phenylephrine-induced constriction and increasing endothelial-dependent dilation of aortic rings from 22-month-ovariectomized Norway rats and decreasing cytokine-stimulated upregulation of adhesion molecules on human aortic endothelial cells [34].…”

Section: Discussionmentioning

confidence: 99%

Enzymatic and free radical formation of cis- and trans- epoxyeicosatrienoic acids in vitro and in vivo

Aliwarga

Raccor

Lemaître

et al. 2017

Free Radical Biology and Medicine

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Epoxyeicosatrienoic acids (EETs) are metabolites of arachidonic acid (AA) oxidation that have important cardioprotective and signaling -6 polyunsaturated fatty acid (PUFA) that is prone to autoxidation. Although hydroperoxides and isoprostanes are major autoxidation products of AA, EETs are also formed from the largely overlooked peroxyl radical addition mechanism. While autoxidation yields both cis- and trans-EETs, cytochrome P450 (CYP) epoxygenases have been shown to exclusively catalyze the formation of all regioisomer cis-EETs, on each of the double bonds. In plasma and red blood cell (RBC) membranes, cis- and trans-EETs have been observed, and both have multiple physiological functions. We developed a sensitive ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay that separates cis- and trans- isomers of EETs and applied it to determine the relative distribution of cis- vs. trans-EETs in reaction mixtures of AA subjected to free radical oxidation in benzene and liposomes in vitro. We also determined the in vivo distribution of EETs in several tissues, including human and mouse heart, and RBC membranes. We then measured EET levels in heart and RBC of young mice compared to old. Formation of EETs in free radical reactions of AA in benzene and in liposomes exhibited time- and AA concentration-dependent increase and trans-EET levels were higher than cis-EETs under both conditions. In contrast, cis-EET levels were overall higher in biological samples. In general, trans-EETs increased with mouse age more than cis-EETs. We propose a mechanism for the non-enzymatic formation of cis- and trans-EETs involving addition of the peroxyl radical to one of AA's double bonds followed by bond rotation and intramolecular homolytic substitution (SHi). Enzymatic formation of cis-EETs by cytochrome P450 most likely occurs via a one-step concerted mechanism that does not allow bond rotation. The ability to accurately measure circulating EETs resulting from autoxidation or enzymatic reactions in plasma and RBC membranes will allow for future studies investigating how these important signaling lipids correlate with heart disease outcomes.

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“…Endothelial senescence is responsible for reduced vascular densities (27) and increased permeability (28), both of which are associated with age-related neurodegenerative diseases. A previous study showed that 14,15-EET mitigates endothelial senescence in mesenteric arterial endothelial cells isolated from aged rats (29). However, whether CYP2J2 can inhibit endothelial senescence still requires further investigation.…”

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confidence: 95%

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

et al. 2019

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Glaucoma is a leading cause of irreversible blindness worldwide. Vascular factors play a substantial role in the pathogenesis of glaucoma. Expressed in the vascular endothelium, cytochrome P450 (CYP) 2J2 is one of the CYP epoxygenases that metabolize arachidonic acid to produce epoxyeicosatrienoic acids and exert pleiotropic protective effects on the vasculature. In the present study, we investigated whether endothelium‐specific over‐expression of CYP2J2 (tie2‐CYP2J2‐Tr) protects against retinal ganglion cell (RGC) loss induced by glaucoma and in what way retinal vessels are involved in this process. We used a glaucoma model of retinal ischemia‐reperfusion (I/R) injury in rats and found that endothelium‐specific overexpression of CYP2J2 attenuated RGC loss induced by retinal I/R. Moreover, retinal I/R triggered retinal vascular senescence, indicated by up‐regulated senescence‐related proteins p53, p16, and β‐galactosidase activity. The senescent endothelial cells resulted in pericyte loss and increased endothelial secretion of matrix metallopeptidase 9, which further contributed to RGC loss. CYP2J2 overexpression alleviated vascular senescence, pericyte loss, and matrix metallopeptidase 9 secretion. CYP2J2 suppressed endothelial senescence by down‐regulating senescence‐associated proteins p53 and p16. These 2 proteins were positively regulated by microRNA‐128‐3p, which was inhibited by CYP2J2. These results suggest that CYP2J2 protects against endothelial senescence and RGC loss in glaucoma, a discovery that may lead to the development of a potential treatment strategy for glaucoma.—Huang, J., Zhao, Q., Li, M., Duan, Q., Zhao, Y., Zhang, H. The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model. FASEB J. 33, 11194–11209 (2019). http://www.fasebj.org

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Inhibitory effect of 14,15-EET on endothelial senescence through activation of mTOR complex 2/Akt signaling pathways

Cited by 17 publications

References 24 publications

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy

Enzymatic and free radical formation of cis- and trans- epoxyeicosatrienoic acids in vitro and in vivo

The effects of endothelium‐specific CYP2J2 overexpression on the attenuation of retinal ganglion cell apoptosis in a glaucoma rat model

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