Hypertension, diabetes, oxidative stress, and cardiovascular remodeling: Making the connection with p66shc

Abstract

An increasing body of evidence suggests that oxidative stress is involved in the pathogenesis of cardiovascular disease, including hypertension and diabetes. In the last few years, new factors playing a major role in oxidative stress signaling and oxidative stress-related responses leading to cardiovascular remodeling, atherogenesis and organ damage have been identified. One of these factors is p66shc which is a splice variant of p52shc/p46shc, adaptor proteins controlling mitogenic signaling from tyrosine kinases to Ras. Although the domain organization is identical in the three isoforms, p66shc shows substantial differences. It does not activate Ras and competitively inhibits signaling by the other isoforms. Furthermore, p66shc is implicated in signaling pathways linking oxidative stress to apoptosis. The major role played by p66shc in oxidative stress-related response has been extensively demonstrated in p66shc knock-out mice which, compared to the wild type, show resistance to oxidative stress, prolonged lifespan, reduction of systemic oxidative stress and oxidative stress induced apoptosis, reduction of plasma LDL oxidation and early atherogenic lesions which are restored by p66shc over-expression, therefore confirming p66shc as a potent inducer of oxidation-sensitive mechanisms. In addition, a link between angiotensin II (Ang II) and p66shc has been demonstrated in an animal model through the protective effect of p66shc genetic deletion on the Ang II-induced myocardial damage, therefore linking this protein with the pathophysiology of hypertension and cardiovascular disease. Studies from our laboratory in humans have been the first to provide information at molecular level of the role of p66shc in the pathophysiology of type 2 diabetes and its complications as well as insulin signaling showing that p66shc is overexpressed in type 2 diabetic patients. Conversely, in a human model of vascular hyporeactivity and increased insulin sensitivity Bartter's/Gitelman's syndrome, which presents a mirror image of hypertension, we have shown that p66shc expression is downregulated. This chapter examines the biology of p66shc, details its involvement in oxidative stress, reports the findings provided by our ongoing studies in humans and, on the basis of the available data, outlines the linkages between p66shc, hypertension, diabetes and cardiovascular remodeling in humans and how these could open possible therapeutic approaches to oxidative stress induced hypertensive and diabetic complications via the pharmacologic targeting of p66shc. © 2008 Springer Netherlands.