DESCRIPTION (provided by applicant): Air pollution is positively associated with an increased daily incidence of myocardial infarction and cardiovascular mortality. Recent findings strongly implicate a role for fresh vehicular exhaust, clearly showing elevated coronary events related acutely to traffic exposure. Clinical and experimental research suggests that air pollutants can acutely induce a vasoconstrictive mechanism, though a clear connection between such studies and the ultimate cardiac sequelae has not been confirmed. The proposed study will seek to validate our previous observations that specific gaseous components of engine exhaust, which are a significant contributor to ambient air pollution, may have pathological vasoactive properties by blunting coronary dilation and enhancing constriction. ECG and vascular abnormalities in ApoE-/- mice occurred when exposed by inhalation to fresh diesel or gasoline exhaust, but not aged, resuspended road dust, suggest that certain compounds in fresh emissions that drive cardiovascular responses may be lost in collected or concentrated particles. Many volatile and semivolatile compounds in fresh emissions can exist in both the gaseous and particulate phases of whole exhaust, and it may be that attempts to ascertain toxicity of filter-collected or concentrated PM may underestimate the adverse health effects by eliminating the gaseous co-pollutants. We have three primary hypotheses to test in this study: (1) We hypothesize that gaseous components of whole emissions can exert effects directly on vascular tissue as well as indirectly by oxidatively modifying endogenous circulating phospholipids, thereby altering the native function of those lipids. Our findings of oxidized low density lipoprotein in the circulation and lipid peroxidation by-products in the vasculature of engine emission-exposed mice, in the absence of overt pulmonary or systemic inflammation suggests that there may be a mild oxidative process in the lung that transfers systemically; (2) We hypothesize that the predominant mechanism driving impaired dilatory function is the formation of peroxynitrite and uncoupling of endothelial nitric oxide synthase. Nitrotyrosine is upregulated in the vasculature following chronic, low-level gasoline exhaust exposure, but it is unknown to what degree peroxynitrite impacts acutely on the vessels; and (3) We hypothesize that observed T-wave abnormalities reflect emission-induced impairment of endothelial cell function, leading to diminished coronary flow and myocardial ischemia in vulnerable subjects. Findings of air pollution-induced rat and mouse ECG abnormalities from several laboratories have not been validated in terms of absolute cardiovascular pathology; we predict diminished coronary flow and mild ischemia will occur in the susceptible mouse strain (ApoE-/-). PUBLIC HEALTH RELEVANCE Cardiovascular effects of air pollution are becoming recognized as a major public health concern. These studies will examine both biological and chemical mechanisms of air pollution-induced adverse coronary events. Results from these studies will assist in the assessment and management of personal risk of health effects from air pollution exposure.