Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR.
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.
Wang
Chao-Yung
CY
Brigham and Women's Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
Kim
Hyung-Hwan
HH
Hiroi
Yukio
Y
Sawada
Naoki
N
Salomone
Salvatore
S
Benjamin
Laura E
LE
Walsh
Kenneth
K
Moskowitz
Michael A
MA
Liao
James K
JK
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
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