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ENDOTHELIAL INJURY IN PARTICULATE MATTER (PM)-INDUCED CARDIOVASCULAR INJURY: KINETIC ANALYSIS OF GENE EXPRESSION PROFILES
Citation:
Nadadur, S. S. AND D L. Costa. ENDOTHELIAL INJURY IN PARTICULATE MATTER (PM)-INDUCED CARDIOVASCULAR INJURY: KINETIC ANALYSIS OF GENE EXPRESSION PROFILES. Presented at Society of Toxicology Annual Meeting, New Orleans, LA, March 06 - 10, 2005.
Description:
Numerous epidemiological studies established positive associations between ambient fine PM and cardiovascular morbidity and mortality. The biological basis for these adverse health effects is yet to be elucidated. Cardiovascular toxicity of fine PM and its toxic constituents may be direct or indirect. Vascular endothelial cells have been implicated in both direct and indirect cardiovascular effects of PM. To understand the role of endothelial injury and dysfunction in PM cardiovascular toxicity, we have initiated in vitro studies using primary human vascular endothelial cells. Acute exposure (25min) to a very low concentration (1mg/ml) of a model emission source PM, residual oil fly ash (ROFA) indicated differential gene expression profile for genes representing various functional groups such as cytokines, growth factors, vascular tone regulators, adhesion molecules, transporter proteins and voltage gated signaling mediators. Molecular observations observed at this early time point predicted alterations in plasma membrane structural and functional properties. Cytological observations at 8h post exposure indicated a role for these genes in the endothelial injury. To further understand the role of continuous exposure of endothelial cells to the same concentration of ROFA, we carried out exposure time kinetic studies at 25 min, 1, 3, 8, 12 and 24h. Gene expression profiles analyzed for ~20,000 genes using human Affymetrix gene chips (H133A) at these time points clearly show time-dependent differential gene expression profiles consistent with progressive endothelial injury and dysfunction. The results of this study may provide insight to understand the role of the endothelium and the molecular basis for PM cardiovascular toxicity. It also may provide a biological basis for the discrepancies observed on the onset of acute myocardial events in cardiac patients associated with that ambient PM exposures. (This abstract does not reflect US EPA policy).