Multiple epidemiological and experimental studies report that acute or chronic exposure to air pollution is associated with adverse cardiovascular events including myocardial ischemia, stroke, arrhythmias, heart failure, sudden cardiac arrest and atherogenesis. These effects of air pollution are most strongly correlated with fine and ultrafine particulate matter (PM) fractions which are generated directly from the combustion of fossil fuels and are found in automobile exhaust, wood or coal smoke and industrial emission from smelters, paper or steel mills or cement plants. A common feature of PM-associated cardiovascular disorders is the establishment and maintenance of a dysfunctional endothelium. Because endothelial dysfunction is an early symptom of cardiovascular disease and an important factor in acute thrombotic complications of atherosclerosis such as stable and unstable angina, myocardial infarction, and ischemic stroke, it could be a key mediator of the cardiovascular toxicity associated with PM exposure. The adult endothelium is a differentiated cell layer that provides a non-thrombotic interface between parenchymal cells and peripheral blood. Damages due to normal wear-and-tear in this layer are repaired by the mobilization and homing of bone-marrow resident pluripotent cells or endothelial progenitor cells (EPCs), which also promote angiogenesis and wound healing. We have recently identified a negative correlation between PM exposure and circulating EPC level. Here, we hypothesize that defects in EPC mobilization or function are a consequence of PM-induced systemic inflammation induced by oxidative stress. We will test this hypothesis in three aims. First we will examine PM-induced changes in EPC populations in the peripheral blood and bone marrow of mice exposed to concentrated ambient air particles (CAPS) or filtered air. We will determine the time course of these effects, whether there is a mobilization defect per se, whether specific populations and locations of EPC are affected and whether this response is selective to EPCs or other stem cells such as the hematopoietic stem cells and mesenchymal stem cells are affected as well. In addition we will measure circulating levels of EPC-derived microparticles to test whether exposure to PM increases EPC activation or cell death.
The second aim i s to delineate the mechanisms by which PM exposure affects EPC function. For this, we will assess how exposure to CAPs affects the ability of EPCs to grow, differentiate, migrate and promote wound healing. We will examine whether these changes in EPC are accompanied by an increase in systemic inflammation and oxidative stress and whether antioxidant interventions or strategies to increase NO availability would prevent PM-induced deficits in EPC number and function. Finally, Aim 3 is to examine whether PM-induced changes in human peripheral blood EPC number and function are accompanied by an increase in systemic inflammation, oxidative stress, and microparticle or miRNA biomarkers and whether anti-oxidant intervention could reverse such changes. Successful completion of this project will provide novel insights into the cardiovascular toxicity of PM and how it affects the abundance and the reparative capacity of stem cells. Findings of this project could also form the basis for the development of new biomarkers of PM exposure or new strategies to mitigate PM toxicity.
Exposure to particulate matter (PM) air pollution is strongly correlated with the initiation and progression of atherosclerosis, increased thrombosis, myocardial infarction, and stroke. These cardiovascular pathologies are characterized by a dysfunctional endothelium and its inefficient repair by pluripotent cells or endothelial progenitor cells (EPCs). Thus in this proposal, we test the hypothesis that the cardiotoxicity resulting from PM exposure is a consequence of PM-induced deficits in EPC number or function.
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