Obesity increases vascular senescence and susceptibility to ischemic injury through chronic activation of Akt and mTOR

CY Wang, HH Kim, Y Hiroi, N Sawada, S Salomone… - Science …, 2009 - science.org
CY Wang, HH Kim, Y Hiroi, N Sawada, S Salomone, LE Benjamin, K Walsh, MA Moskowitz
Science signaling, 2009science.org
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 …
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.
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