Abstract 116: Mechanism of ApoA-I Attenuation of Inflammation Associated with Atherosclerosis

Cytokines/chemokines and their receptors have been an important consideration when investigating the role of inflammation in atherosclerosis. In humans and animal models, monocyte recruitment and accumulation within the artery wall occurs in response to elevated plasma cholesterol levels. To mimic this process in a mouse model of atherosclerosis, our lab has utilized the LDLr-/-, ApoA-I-/- double knockout mouse. Our studies have shown that LDLr-/-, ApoA-I-/- mice have increased immune cell mobilization driving the progression of atherosclerosis when compared to LDLr-/- mice, and that treating mice with frequent, low doses (200 μg) of subcutaneous administered lipid-free apoA-I or rHDL reverses the atherogenic process. Based on these studies we wanted to investigate which inflammatory pathways were most affected by apoA-I treatment. To do this, we carried out RT-PCR to obtain the relative mRNA abundance on 40 different markers of inflammation in two genotypes of atherogenic diet fed mice. Each genotype of mice was divided into two subsets. One subset was fed an atherogenic diet for 12 weeks while the other subset received 12 weeks of diet and subcutaneous injections of 200 μg of apoA-I for the last 6 weeks of the study. Spleen was isolated from all animals and their inflammatory gene mRNA expression examined. Most significantly both genotypes showed a large decrease in IL-3 mRNA expression but also showed a significant increase in CD163 mRNA expression with apoA-I treatment. Decrease in splenic IL-3 expression is a significant mediator of inflammation regression because of the role IL-3 plays in monocyte production inside the spleen. Other investigators have shown that myeloid cells reserved in the spleen give rise to monocytes in an IL-3 rich environment. IL-3 develops and maintains circulating monocytes, which may accumulate in the arteries during atherosclerosis. This suggests apoA-I treatment affects IL-3 levels in the spleen, and thus the amount of monocytes in circulation. An increase in CD163 mRNA expression in the spleen implies higher accumulation of monocytes inside the spleen, and out of circulation. This suggests that apoA-1 treatment can decrease the amount of monocytes in the arteries, which can be a result of reverse in the atherogenic process.