Extensive epidemiological data suggest that exposure to aldehydes or aldehyde-generating pollutants increases the risk of cardiovascular disease. However, the mechanisms by which aldehydes affect cardiovascular health are not known. We propose that exposure to environmental aldehydes such as acrolein or trans-2-hexenal exacerbates arteriosclerosis. Based on our preliminary results, we suggest that aldehyde exposure leads to lipoprotein modification, which induces vascular inflammation, and dysregulates cell growth, thereby resulting in the formation of more extensive, unstable, and cellular lesions. To test this hypothesis in Specific Aim 1 we will examine how exposure to inhaled acrolein or dietary hexenal or acrolein affects the progression of atherogenesis in wild type, apoE and low-density lipoprotein receptor- null mice. We will also determine whether the atherogenecity of aldehydes is modulated by the extent of hypercholestremia.
The second aim of the project is to elucidate aldehyde-induced changes in lipoproteins. For this, we will examine the severity and the extent of lipoprotein changes in aldehyde-exposed mice and test whether aldehyde exposure causes modification, cross-linking or aggregation of lipoproteins and elicits the development of autoantibodies against protein-aldehyde adducts.
Our final aim i s to delineate the atherogenic consequences of aldehyde-induced lipoprotein modification. We will establish whether modifications due to aldehyde exposure increase the atherogenicity of lipoproteins, and whether aldehydes disrupt cholesterol metabolism by preventing the maturation of the HDL (high-density lipoprotein) particle. Finally, we will examine whether the aldehyde-induced dyslipidemia is due to the inhibition of lecithin: cholesterol acyl transferase (LCAT) and if the dyslipidemic changes are diminished in LCAT-deficient mice. Together the results of this project will provide new information about the effects of the most toxic and abundant pollutants in the environment on arteriosclerosis, and reveal mechanisms by which they contribute to the risk of heart disease - which is the leading cause of death in the industrialized world. Successful completion of these studies will form the basis of future assessment of human risk and susceptibility.
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