Abstract 1314: Atherogenic Gene Expression Correlates with Subsequent Variable Lesion Development in Coronary and Peripheral Vessels
Background: The sequence of specific gene regulation and subsequent atherosclerosis development are not completely understood. We hypothesized that genes related to vascular cholesterol handling, inflammatory and insulin pathway responses are differentially regulated in a site-specific and time dependent manner. We tested this hypothesis in the diabetic-hypercholesterolemic (DM/HC) swine model which develops complex coronary lesions within 6 months.
Methods: Swine (n=52) made diabetic and hypercholesterolemic were sacrificed at 1, 3, 6 and 9months. Histological evaluations were evaluated at baseline, 1, 3 and 6 months after induction. Gene expression was investigated by “Real-Time PCR.”
Results: Progressive atherosclerotic lesion development was observed in the coronary arteries with minimal lesion development noted in the carotid arteries and thoracic aortae. 6–9 months of DM/HC resulted in increased coronary lesion complexity with 83% of arteries exhibited Stary/AHA grade IV or higher and 89% exhibited complex disease by the Virmani criteria. Gene expression was altered primarily in the coronary arteries rather than the other 2 territories and included those involved in lipid metabolism (upregulated: ABCA1; downregulated: fatty acid synthase and PPARα mRNAs), inflammatory (upregulated: Lp-PLA2, ICAM-1, VCAM-1, CCR1, CCL2, IL-1R, NOS2A mRNAs) and insulin pathways (upregulated: adiponectin, leptin, PPARγ, IRS1 mRNAs). Examples of genes which were increased significantly at 1 month and maintained thereafter included ICAM-1, NOS2A and ABCA1 whereas genes related to plaque instability (e.g. MMP-9, uPAR, CCL2 and Lp-PLA2 mRNAs) appeared later (i.e. 6 months) and were increased in coronary arteries but not carotid and aortae.
Conclusions: This is the first study demonstrating the temporal change in gene expression in an atherosclerotic large animal model and correlation with plaque development and progression. The temporal relationship between gene expression and eventual lesion development may provide further insight into the atherosclerotic process and development of new therapeutic targets.