Relationship of the 20S proteasome and the proteasome activator PA28 to atherosclerosis and intimal hyperplasia in the human vascular system

Down-regulation of the proteasome activator PA28 results in abnormal protea some activation and has been implicated in the development of intimal hyper plasia (IH) in animal models. Demonstration of proteasome and PA28 expressi on has not yet been documented in the human vascular system. This study sou ght to define the distribution of the 20S proteasome and its activator PA28 in human vessels and determine the relationship between the expression of the proteasome and PA28 and the development of atherosclerosis and IH. Vasc ular biopsies were obtained from 70 patients at the time of surgery, were s nap frozen and sectioned in 5-mum sections, and prepared using standard his tological techniques. The immunoperoxidase technique was used to identify 2 0S proteasome and PA28 expression in diseased and normal human arteries and veins as well as in patent bypass grafts with and without IH. Expression w as graded by a blinded pathologist (scale: 1-4). Repeat quantification of t he immunopositive cells was also performed. Expression of 20S proteasome an d PA28 was identified in all vascular tissues examined. The proteins were i dentified predominately within the cytoplasm of vascular smooth muscle cell s and endothelial cells. PA28 was more intensely expressed in quiescent reg ions of the vessel wall as compared to areas undergoing active proliferatio n and remodeling. PA28-mediated activation of the proteasome may be necessa ry to maintain normal cellular homeostasis and prevent excessive cellular p roliferation in the human vascular system. Abnormalities of proteasome acti vation may have a significant role in the development of atherosclerosis an d IH.