Reactive nitrogen species and cardiovascular aging

Marton, Anita

Abstract

This pilot grant application is submitted to explore certain aspects of free radical and oxidant mediated alterations of vascular function associated with aging. Endothelial injury and vascular dysfunction associated with aging is related to local, free radical-related processes, and plays a role in the pathogenesis of various vascular complications associated with aging (including atherosclerosis). Pharmacological modulation of this endothelial cell death and injury may provide novel avenues for the experimental therapy for the vascular dysfunction associated with aging. We have obtained preliminary data in cultered endothelial cells that oxidants proceeded in the vicinity of endothelial cells trigger an intracellular cascade culminating governed by the nuclear enzyme poly (ADP-ribose) synthetase (PARS). This results in activation of PARS which initiates an energy consuming cycle, with resultant cell dysfunction and impaired endothelial nitric oxide generation. Our preliminary data also demonstrated that pharmacological inhibition or genetic inactivation of PARS reduces the development of oxidant- mediated endothelial injury. In the current pilot research project we venture into the area of aging to explore the importance of the peroxynitrite/PARS pathway in aging blood vessels. Our working hypothesis is that in the aging vasculature, due to the reduced anti- oxidant capacity, and the increased oxidant generation, reactive nitrogen species formation and PARS activation occurs. In the first aim of the study, by comparing reactive nitrogen species generation, vascular reactivity and PARS activation in the blood vessels from adult and aged rats, we will explore the time course of the activation of the above described pathway. In the second specific aim, chronic treatment with pharmacological inhibitors of PARS will address the question whether PARS contributes to the loss of endothelial function associated with aging. Our studies will provide 1. novel mechanistic information on aging-related endothelial dysfunction and 2. preliminary data for a subsequent full grant application to study the peroxynitrate/PARS pathway in the process of vascular aging.