title: Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR.
abstract: Obesity and age are important risk factors for cardiovascular disease. However, the signaling mechanism linking obesity with age-related vascular senescence is unknown. Here we show that mice fed a high-fat diet show increased vascular senescence and vascular dysfunction compared to mice fed standard chow and are more prone to peripheral and cerebral ischemia. All of these changes involve long-term activation of the protein kinase Akt. In contrast, mice with diet-induced obesity that lack Akt1 are resistant to vascular senescence. Rapamycin treatment of diet-induced obese mice or of transgenic mice with long-term activation of endothelial Akt inhibits activation of mammalian target of rapamycin (mTOR)-rictor complex 2 and Akt, prevents vascular senescence without altering body weight, and reduces the severity of limb necrosis and ischemic stroke. These findings indicate that long-term activation of Akt-mTOR signaling links diet-induced obesity with vascular senescence and cardiovascular disease.
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
authors.forename: Chao-Yung
authors.initials: CY
authors.lastname: Wang
authors.forename: Hyung-Hwan
authors.initials: HH
authors.lastname: Kim
authors.forename: Yukio
authors.initials: Y
authors.lastname: Hiroi
authors.forename: Naoki
authors.initials: N
authors.lastname: Sawada
authors.forename: Salvatore
authors.initials: S
authors.lastname: Salomone
authors.forename: Laura E
authors.initials: LE
authors.lastname: Benjamin
authors.forename: Kenneth
authors.initials: K
authors.lastname: Walsh
authors.forename: Michael A
authors.initials: MA
authors.lastname: Moskowitz
authors.forename: James K
authors.initials: JK
authors.lastname: Liao
mesh_terms: D000818:Animals; D002318:Cardiovascular Diseases / Q000209:etiology*; D002352:Carrier Proteins / Q000378:metabolism*; D016922:Cellular Senescence / Q000187:drug effects / Q000502:physiology*; D004198:Disease Susceptibility / Q000209:etiology; D004435:Eating; D004789:Enzyme Activation / Q000187:drug effects; D007511:Ischemia / Q000209:etiology*; D051379:Mice; D008822:Mice, Transgenic; D009765:Obesity / Q000150:complications*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D002352:Carrier Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C546843:mTOR protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus