Obesity predisposes to cardiovascular disease, which is the primary cause of death in the obese population.During the current period of support, results demonstrate that coplanar PCB ligands of the arylhydrocarbonreceptor (AhR), which accumulate markedly in adipose tissue, increase adipocyte differentiation andproinflammatory gene expression. Administration of PCB77 to apolipoprotein E (apoE)-/- mice resulted in anincrease in body weight, adipose mass, and macrophage imrnunostaining in adipose tissue. Importantly,mice administered PCB77 exhibited a marked increase in their susceptibility to angiotensin II (Angll)-inducedabdominal aortic aneurysm (AAA) formation. We have previously demonstrated that Angll-induced AAAsare associated with marked inflammation in vascular and surrounding peri-aortic adipose tissue, and thatobesity increases the susceptibilty to Angll-induced AAAs. The working hypothesis of this proposal is thatadiposity and proinflammatory adipokine expression in response to coplanar PCBs promotes Angll-inducedAAAs. Moreover, we hypothesize that dietary manipulation of fat content will modulate the adverse effects ofcoplanar PCBs on Angll-induced AAAs.
In aim 1, we will identify mechanisms for coplanar PCB-inducedregulation of proinflammatory gene expression in adipocytes, focusing on oxidative stress and NFkappaB assignaling intermediates. Given that adipocytes store fatty acids, we will examine the interplay betweenpolyunsaturated fatty acids (PUFA) of the n-6 versus n-3 family in their ability to promote or abrogate theeffects of coplanar PCBs.
In aim 2 we will define the role of the adipocyte AhR in the effects of PCB77 onproinflammatory adipokine expression, body weight, and Angll-induced AAAs.
In aim 3 we will determinethe effect of diets enriched with linoleic acid (n-6) or linolenic acid (n-3) on PCB77-induced regulation of bodyweight, ectopic lipid deposition and the formation and progression of Angll-induced AAAs. Results fromthese studies will directly relate to all projects of this superfund, through elaboration of mechanisms wherebydietary intervention through fatty acids can mitigate or augment the toxicity of PCBs on the vascular system,on the ability to measure and detect PCBs in biological samples, and on the pathophysiologic effects of PCBremediation products on adipocyte and vascular function. The long-term health benefits of this researchrelate to definition of contribution of PCBs to obesity and to obesity-associated cardiovascular disease.
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