Final common molecular pathways of aging and cardiovascular disease: role of the p66Shc protein.
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 p66(Shc) 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 p66(Shc) and its possible implication in cardiovascular diseases. Indeed, p66(Shc-/-) 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 p66(Shc) adaptor protein as well as on the mechanisms linking p66(Shc)-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 p66(Shc) 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.
Cosentino
Francesco
F
Cardiology and Cardiovascular Research, University Hospital, Zürich, Institute of Physiology, University of Zürich, and Center for Integrative Human Physiology (ZIHP), Switzerland.
Francia
Pietro
P
Camici
Giovanni G
GG
Pelicci
Pier Giuseppe
PG
Lüscher
Thomas F
TF
Volpe
Massimo
M
D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002318:Cardiovascular Diseases / Q000209:etiology* / Q000378:metabolism; D003925:Diabetic Angiopathies / Q000209:etiology / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D008955:Models, Cardiovascular; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1
D048868:Adaptor Proteins, Signal Transducing; D017382:Reactive Oxygen Species; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1