title: Rapamycin inhibits hydrogen peroxide-induced loss of vascular contractility.
abstract: Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR) pathway, has been shown to extend the life span of mice, and oxidative stress plays critical roles in vascular aging involving loss of compliance of arteries. We examined, therefore, whether rapamycin has protective effects on the inhibition of vascular contractility by hydrogen peroxide (H₂O₂). Prolonged (3 h) exposure to H₂O₂ induced complete loss of contraction of mouse aortic rings and mesenteric (resistance) arteries to either KCl or phenylephrine, which was attenuated by pretreatment with rapamycin. H₂O₂-induced loss of contractility was unaffected by treatment with actinomycin D or cycloheximide, inhibitors of gene transcription and protein synthesis, respectively. Western blot analysis showed that there was no increase in phosphorylation of S6 kinase 1 (S6K) or factor 4E binding protein 1 (4EBP1) in response to H₂O₂ treatment, suggesting involvement of the mTOR complex-2 (mTORC2) rather than mTORC1. H₂O₂ treatment inhibited phosphorylation of the 20-kDa regulatory light chains of myosin (LC₂₀), which was partially blocked by rapamycin treatment. Interestingly, the calcineurin inhibitors cyclosporine A and FK506 were found to mimic the rapamycin effect, and rapamycin inhibited calcineurin activation induced by H₂O₂. We conclude that rapamycin inhibits H₂O₂-induced loss of vascular contractility, likely through an mTORC2-calcineurin pathway.
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Medicine, Univ. of Calgary, Calgary, Alberta, Canada.
authors.forename: Ge
authors.initials: G
authors.lastname: Gao
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Li
authors.forename: Yuenan
authors.initials: Y
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Yuebing
authors.initials: Y
authors.lastname: Wang
authors.forename: Lifeng
authors.initials: L
authors.lastname: Wang
authors.forename: Xiang D
authors.initials: XD
authors.lastname: Tang
authors.forename: Michael P
authors.initials: MP
authors.lastname: Walsh
authors.forename: Yu
authors.initials: Y
authors.lastname: Gui
authors.forename: Xi-Long
authors.initials: XL
authors.lastname: Zheng
mesh_terms: D000375:Aging / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000502:physiology; D065095:Calcineurin Inhibitors; D016572:Cyclosporine / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D016877:Oxidants / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D016559:Tacrolimus / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology
chemical_list: D065095:Calcineurin Inhibitors; D007166:Immunosuppressive Agents; D016877:Oxidants; D016572:Cyclosporine; D006861:Hydrogen Peroxide; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus; D016559:Tacrolimus