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THE ROLE OF OXIDATIVE STRESS AND CARDIOVASCULAR DISEASE IN SUSCEPTIBILITY TO CARDIOVASCULAR AND PULMONARY EFFECTS OF PARTICULATE MATTER (PM) AND PM CONSTITUENTS.
Impact/Purpose:
This project will provide mechanistic information on the role of underlying oxidative stress as a risk factor for exacerbated PM responses in compromised animal model of human cardiovascular disease. Specifically, this work will support efforts to (1) Identify potential PM cause components for cardiac injury and mechanisms; (2) Define the role of oxidative stress in susceptibility to combustion derived PM and metal constituents; (3) Define the role of hypertension/cardiovascular disease in susceptibility to combustion derived PM and metal constituents; and (4) Identify the role of pulmonary microvascular thrombosis in casing systemic and cardiovascular effects of model PM.
Description:
Underlying oxidative stress has been one of the major risk factors for cardiopulmonary diseases in humans. We have shown that Spontaneously Hypertensive rats, similar to humans, possess systemic oxidative stress associated with hypertension and can not respond to PM-induced injury by increasing antioxidants unlike healthy Wistar Kyoto rats. In this project we are investigating the role of oxidative stress in exacerbation of cardiopulmonary injury by intervening oxidative stress and cardiovascular disease to understand its involvement in susceptibility. Rats are supplemented with antioxidants known to alleviate oxidative stress and subsequently exposed to PM or suspect PM constituents. Acute and long-term PM exposure studies are being conducted. The hypothesis that cardiac mitochondrial oxidative stress underlies PM-cardiac injury and susceptibility is also being investigated. The underlying changes in MAP kinase, NRF2 signaling (major signaling pathway sensitive to oxidative stress), microvascular thrombosis and gene expression profiles of the lung and the heart are studied to understand biological pathways that are responsible for oxidative stress mediated compensatory failure in PM susceptibility. This project will provide mechanistic information on how underlying cardiovascular disease and oxidative stress may predispose humans to exacerbated disease, thrombosis or death when exposed to PM and aid in identification of PM constituents responsible for specific or common effects.