on December 27, 2007
Published online before print December 27, 2007, doi: 10.1161/ATVBAHA.107.156059
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Submitted on September 15, 2007
Accepted on December 14, 2007
Final Common Molecular Pathways of Aging and Cardiovascular Disease. Role of the p66Shc Protein
Francesco Cosentino ;
From Cardiology and Cardiovascular Research (F.C., G.G.C., T.F.L.), University Hospital, Zurich, Institute of Physiology, University of Zurich, Switzerland; Cardiology, 2nd Faculty of Medicine (F.C., P.F.), University "La Sapienza", Rome, Italy; Arrhythmia and Electrophysiology Centre (P.F.), I.R.C.C.S. San Donato, University of Milan, Italy; and Experimental Oncology (P.G.P.), European Institute of Oncology, Milan, Italy.
* To whom correspondence should be addressed. E-mail: karlue{at}usz.unizh.ch.
Abstract—Oxidative stress affects the availability of key-regulators of vascular homeostasis and controls a number of signaling pathways relevant to myocardial and vascular disease. Reactive oxygen species are generated by different intracellular molecular pathways principally located in mitochondria. The notion that mice carrying a targeted mutation of the p66Shc gene display prolonged lifespan, reduced production of intracellular oxidants, and increased resistance to oxidative stress–induced apoptosis prompted a series of studies aimed at defining the biochemical function of p66Shc and its possible implication in cardiovascular diseases. Indeed, p66Shc-/- mice are protected against vascular, cardiac, and renal impairment attributable to hypercholesterolemia, aging, diabetes, and ischemia/reperfusion. The present review focuses on the biochemical and physiological function of the p66Shc adaptor protein as well as on the mechanisms linking p66Shc-associated generation of free radicals to the pathophysiology of aging and cardiovascular disease. On the whole, the evidence so far reported and here discussed supports the concept that pharmacological modulation of p66Shc expression and activity may be a novel and effective target for the treatment of atherosclerotic vascular disease as well as myocardial adaptation to hypertrophic, inflammatory and neuro-hormonal stimuli in the overloaded heart.
Key words: p66Shc • aging • atherosclerosis • diabetes • energy metabolism
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