New aspects of p66Shc in ischemia reperfusion injury and cardiovascular diseases

Abstract

Although reactive oxygen species (ROS) act as crucial factors in the onset and progression of a wide array of diseases, they are also involved in numerous signal pathways related to cell metabolism, growth and survival. ROS are produced at various cellular sites and a general consensus exists that mitochondria generate the largest amount, especially in cardiomyocytes. However, the identification of the most relevant sites within mitochondria, the interaction among the various sources, and the events responsible for the increase in ROS formation under pathological conditions remain issues that are highly debated, but far from convincing conclusions. Here, we review information linking the adaptor protein p66Shc with cardiac injury induced by ischemia and reperfusion (I/R), including the contribution of risk factors, such as metabolic syndrome and aging. In response to several stimuli, p66Shc migrates into mitochondria where it catalyzes electron transfer from cytochrome c to oxygen resulting in hydrogen peroxide formation. Deletion of p66Shc has been shown to reduce I/R injury as well as vascular abnormalities related to diabetes and aging. On the other hand, p66Shc-induced ROS formation is involved in insulin signaling and might contribute to self-endogenous defenses against mild I/R injury. Besides physiological and pathological aspects, for the first time available information is reviewed on compounds or conditions modulating p66Shc expression and activity.