title: Inhibitory effect of 14,15-EET on endothelial senescence through activation of mTOR complex 2/Akt signaling pathways.
abstract: Therapies to reverse the vascular endothelial aging process may play as a novel strategy for the treatment of cardiovascular diseases. 14,15-epoxyeicosatrienoic acid (14,15-EET) is a predominant cytochrome P450 epoxygenases-derived arachidonic acid metabolite and possesses multiple biological effects on the vascular system. The present study sought to investigate the roles of mammalian target of rapamycin complex 2 (mTORC2)/Akt signaling pathways in mediating the effect of 14,15-EET on endothelial senescence. By measuring the isometric tension in rat mesenteric arteries, we demonstrated that 14,15-EET improved the impaired endothelium-dependent vasodilatation in aged rats through activating mTORC2/Akt signaling pathway. Meanwhile, by promoting the formation of mTORC2 and the phosphorylation of Akt (Ser473), 14,15-EET inhibited the senescence of rat mesenteric arterial endothelial cells, which was not influenced by rapamycin but was significantly attenuated by Akt1/2 kinase inhibitor. The knockdown of Rictor gene by RNA interference abolished the inhibitory effect of 14,15-EET on endothelial senescence. Furthermore, 14,15-EET down-regulated the expression of p53 protein in aged endothelial cells. Meanwhile, the nuclear translocation of telomerase reverse transcriptase and the nuclear telomerase activity were also enhanced by treatment with 14,15-EET. Therefore, our present study suggests the crucial role of mTORC2/Akt signaling pathways in the inhibitory effects of 14,15-EET on the endothelial senescence. Our findings reveal important mechanistic clues to understanding of the effects of 14,15-EET on the endothelial functions.
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China. Electronic address: yangynni@163.com.
authors.forename: Cui
authors.initials: C
authors.lastname: Yang
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China.
authors.forename: Shitian
authors.initials: S
authors.lastname: Pan
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China.
authors.forename: Saimei
authors.initials: S
authors.lastname: Yan
authors.affiliation: Laboratory of Pharmacology and Toxicology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou 510006, PR China.
authors.forename: Zhuoming
authors.initials: Z
authors.lastname: Li
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China.
authors.forename: Jinyan
authors.initials: J
authors.lastname: Yang
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Ethnic Drug Screening & Pharmacology Center, Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Yunnan University of Nationalities, Kunming 650500, PR China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Xiong
mesh_terms: D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D000367:Age Factors; D000818:Animals; D016922:Cellular Senescence / Q000187:drug effects; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008297:Male; D000076225:Mechanistic Target of Rapamycin Complex 2; D008638:Mesenteric Arteries / Q000166:cytology; D046912:Multiprotein Complexes / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D046912:Multiprotein Complexes; C046782:14,15-epoxy-5,8,11-eicosatrienoic acid; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D015126:8,11,14-Eicosatrienoic Acid
keywords: 14,15-Epoxyeicosatrienoic acid; Aging; Endothelial cells; Mammalian target of rapamycin; Rictor