W156 - Over Expression of GATA2 in Atherogenic Macrophage Induce Development of Atherosclerosis

Minhyuk Mun – University of Western Ontario; Kasia Wodz – University of Western Ontario; Angela Vrieze – University of Western Ontario; A Dave Nagpal – University of Western Ontario; Bryan Heit – University of Western Ontario

Abstract Text: The loss of efferocytic activity – the phagocytic clearance of apoptotic cells – in cardiac macrophages is required for the accumulation of necrotic cells that causes atherosclerotic plaque. Our lab demonstrated that defects in macrophage efferocytosis occur by over-expression of hematopoietic transcription factor GATA2. In this study, we investigated the pathways that regulate GATA2 expression in macrophages and identified the GATA2-regulated genes that promote atherogenesis.
We found higher GATA2 expression in the circulating monocytes of ~50% of atherosclerosis patients. However, there was no correlation between monocytic GATA2 expression, plasma cytokines, monocyte intravascular recruitment, or monocyte proliferation. However, PDGF-AB/BB was elevated in some patients, and in vitro, this induced GATA2 expression in macrophages. There was no correlation between monocyte GATA2 expression and plaque macrophage GATA2 expression, with GATA2-expressing macrophages identified in the plaques of all patients. In the plaque, GATA2 drives the proliferation of macrophages and reduces their sensitivity to apoptosis. Although GATA2 can be expressed from two promoters, we determined that only the internal (IG) promoter is used by macrophages. We also determined that atherogenic stimuli induces GATA2 expression from the IG promoter via NF-кB, Ahr, and STAT1, while AP-1 negatively regulates GATA2 expression. ChIP-seq identified the GATA2 transcriptome, which include MIR12136, a microRNA that negatively regulates a plethora of efferocytic receptors, apoptosis-regulatory proteins, and proteins required for the degradation of engulfed apoptotic cells.
This study provides further insights into the mechanism by which GATA2 impairs efferocytosis during atherosclerosis and may identify future therapeutic targets for the treatment of atherosclerosis.