Abstract
Abstract Atherosclerosis is an inflammatory disease involving formation of lipid-rich lesions within the arteries. Macrophages clear apoptotic cells that accumulate within these lesions. Defective apoptotic cell clearance is a hallmark of advanced atherosclerotic disease, yet mechanisms that drive this defect are poorly understood. In this study, we identify the hematopoietic transcription factor GATA2 as a novel regulator of macrophage-mediated apoptotic cell clearance. Macrophages were isolated by laser capture microdissection from atherosclerotic lesions in aortic tissue obtained from patients undergoing open heart surgery. Gene expression profiling was performed on these macrophages by microarray, with macrophages derived from peripheral blood monocytes used as a control. We found approximately 3,000 genes to be differentially expressed in aortic punch macrophages, with enrichment in pathways involved in apoptotic cell clearance. In particular, we identified upregulation of GATA2. Mutations in GATA2 have previously been associated with increased risk of coronary artery disease and we found that overexpression of GATA2 in vitro resulted in decreased ability of macrophages to both internalize and degrade apoptotic cells. Conversely, GATA2 downregulation is sufficient to abrogate oxLDL-induced defective apoptotic cell clearance. Atherosclerotic macrophages exhibit dysregulated expression of genes involved in apoptotic cell clearance and upregulation of GATA2. Recapitulation of GATA2 overexpression is sufficient to impair apoptotic cell clearance in vitro. To our knowledge, we are the first to identify a potential role for GATA2 in driving defective apoptotic cell clearance in atherosclerosis.
Published Version
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