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Sci. Signal., 17 March 2009
Vol. 2, Issue 62, p. ra11
[DOI: 10.1126/scisignal.2000143]

RESEARCH ARTICLES

Obesity Increases Vascular Senescence and Susceptibility to Ischemic Injury Through Chronic Activation of Akt and mTOR

Chao-Yung Wang1, Hyung-Hwan Kim1, Yukio Hiroi1, Naoki Sawada1, Salvatore Salomone2, Laura E. Benjamin3, Kenneth Walsh4, Michael A. Moskowitz2, and James K. Liao1*

1 Vascular Medicine Research Unit, Brigham and Women’s Hospital and Harvard Medical School, Cambridge, MA 02139, USA.
2 Stroke and Neurovascular Regulation Laboratory, Department of Neurology and Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02139, USA.
3 Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
4 Molecular Cardiology/Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA 02118, USA.

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.

* To whom correspondence should be addressed. E-mail: jliao{at}rics.bwh.harvard.edu

Citation: C.-Y. Wang, H.-H. Kim, Y. Hiroi, N. Sawada, S. Salomone, L. E. Benjamin, K. Walsh, M. A. Moskowitz, J. K. Liao, Obesity Increases Vascular Senescence and Susceptibility to Ischemic Injury Through Chronic Activation of Akt and mTOR. Sci. Signal. 2, ra11 (2009).

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