Abstract 19264: Regression of Atherosclerosis is Characterized by Molecular Re-programming of the Transcriptome: Insights into the Identification of New Therapeutic Targets Against Cardiovascular Disease
Atherosclerosis is the leading underlying cause of strokes and myocardial infarctions worldwide. We reported a mouse model of atherosclerosis regression that involves transplanting an atherosclerotic aortic arch into a normolipidemic mouse. The CD68+ cell population (predominantly macrophages) in the regressing plaques exhibited migratory behavior. To identify pathways and factors responsible for the beneficial changes in macrophage content and phenotype in the regressing plaques, we performed microarray analysis on RNA purified from laser captured CD68+ plaque cells isolated from atherosclerosis progression and regression environments. This yielded two major findings. First, genes associated with the contractile apparatus (such as titin, actinin and myopalladin) that are responsible for cellular movement were differentially up-regulated under regression conditions (by 3-4 fold) with members of the cadherin family (serves in adhesion functions) being significantly down-regulated by 2-3 fold. Both changes are consistent with the macrophage migratory behavior we observed in the regression environment. Secondly, the most highly up-regulated gene under regression conditions was arginase I (~8 fold), a classical marker of the M2 alternatively activated macrophage. Further examination revealed that regression was characterized by macrophages displaying other M2 markers, such as CD163, C-lectin receptor, mannose receptor, and Fizz-1, consistent with a less inflammatory state in the regression environment. In addition, we applied recently introduced local causal pathway discovery methods to the microarray data that revealed that vinculin and ApoCII, known factors in cell adhesion and lipid metabolism, respectively, may be important regulators in the pathophysiology of atherosclerosis regression. Ultimately, the insights gained from the regression model and the different modes of global analyses should lead to new therapeutic targets against cardiovascular disease.
- © 2012 by American Heart Association, Inc.