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Superfund Research Program

Combustion-Generated Ultrafine Particles: Cardiovascular and Cardiac Effects (ARRA Funded)

Project Leader: Kurt J. Varner
Grant Number: P42ES013648
Funding Period: 2009-2011

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Project Summary (2009-2011)

Elevations in airborne particulate matter (PM) are associated with increased cardiac/cardiovascular morbidity and mortality, especially in individuals with existing cardiovascular disease. In spite of the correlation between PM and cardiac disease, the mechanisms underlying these toxic responses are unknown. Ultrafine PM (UFP) contains toxic organic species and metals that form surface-stabilized, persistent free radicals (PFRs). Dr. Varner’s data show that PFR/UFP systems can increase oxidative stress (OS) in vitro and in vivo. Since OS is also an important mediator of cardiac/cardiovascular disease, the researchers hypothesize that: PFR/UFP systems produced by combustion/thermal degradation of hazardous wastes produce cardiac toxicity by increasing OS in the heart, and that the toxicity of UFP will be enhanced in the presence of underlying cardiac or pulmonary disease in which OS plays an important pathophysiological role.

This project will address three specific aims:

Specific Aim 1 will compare the cardiac/ cardiovascular responses elicited by the acute and repeated administration of UFP in rats subject to cardiac ischemia/reperfusion (I/R) injury or sham. Radio telemetry will be used to monitor arterial pressure, heart rate and electrocardiographic responses elicited by administration of the chlorophenoxyl PFR of 2-monchlorophenol associated with a UFP of CuO/silica in I/R injured rats produced by transient occlusion of the lower anterior descending coronary artery. Serial echocardiograms and pressure-volume conductance catheters will monitor cardiac structure/function during and after UFP exposure. Heart rate variability will be used to determine whether exposure to UFP alters autonomic control of the heart.

Specific Aim 2 will compare the cardiac/ cardiovascular responses elicited by the acute and repeated administration of UFP in control rats and rats having chronic obstructive pulmonary disease (COPD). Cardiac and cardiovascular function will be assessed in control and COPD rats as described above.

Specific Aim 3 will identify the mechanisms by which UFP produces OS and cardiac toxicity in vivo. Biochemical, proteomic analyses, and histology will be used to measure nitrotyrosine content, identify redox-modified lipids and proteins, look for changes in radical producing and scavenging enzymes, and search for evidence of cardiac apoptosis and inflammation.

This project will elucidate mechanisms by which UFP produce OS and cardiac toxicity in "at risk" populations.

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