Tobacco use and atherosclerosis protection by paraoxonase
Abstracts
Initial Award Abstract |
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Atherosclerosis is the major cause of death in Western nations. A major risk factor for atherosclerosis is exposure to tobacco smoke. This exposure comes from direct use of tobacco products as well as indirect or passive contact with environmental tobacco smoke (ETS). The toxicity of tobacco smoke is due to multiple agents including oxidants and inducers of reactive oxygen species. These reactive species can initiate oxidative damage of phospholipids present in plasma lipoproteins. Published studies have demonstrated that exposure of hypercholesterolemic mice to ETS will exacerbate atherosclerosis lesion progression.
A protective plasma enzyme, which travels on high density lipoprotein (HDL) and can destroy and neutralize oxidized phospholipids, is paraoxonase1 (PON1). Transgenic expression of PON1 by macrophages (MN) protects hypercholesterolemic, low density lipoprotein receptor deficient (LDLr-/-) mice from atherosclerosis. In published studies male LDLr-/- mice were given bone marrow transplants (BMT) from PON1 transgenic donor mice. The recipient mice had 40% less lesion areas in their aortic sinus lesions compared to recipient LDLr-/- mice that received bone marrow from non transgenic littermates. When repopulation of the BMT LDLr-/- mice was enhanced by their treatment with gadolinium chloride, they exhibited even greater protection from diet-induced atherosclerosis.
This proposal is testing the hypothesis that MN expression of PON1 will reduce the generation of oxidized phospholipids in ETS-exposed mice and protect them from ETS-exacerbated atherosclerosis. We wish to determine the atheroprotective effects of the local expression of PON1 by bone marrow-derived circulating monocytes and lesion MN in BMT, LDLr-/- mice exposed to ETS. Our recent data show that in a control experiment, GFP-transgenic mice exposed to 30mg/m3 of environmental tobacco smoke develop as much lesions as mice exposed to filtered air. We have therefore increased the environmental tobacco smoke exposure to 60mg/m3. The increase in environmental tobacco smoke exposure resulted in decreased weight gain and higher total plasma cholesterol levels after eight weeks of exposure.
We hope to demonstrate that ETS aggravates atherosclerotic lesion development and that MN expression of PON1 is atheroprotective. If successful these studies will identify a permanent gene transfer treatment strategy for persons who are at risk for atherosclerosis aggravated by active or passive exposure to tobacco smoke. |
