GATA2 Mediates Macrophage Proliferation During Atherosclerosis.

BACKGROUND

Atherosclerosis is fueled by the buildup of lipid-laden macrophages within the vascular intima. These macrophages are derived from monocytes that are recruited from the circulation into the developing lesion, where they proliferate and differentiate into macrophages, with local proliferation generating most of these macrophages. However, the signals and transcriptional events driving the proliferation of atheroma macrophages remain poorly understood.

METHODS

Transcriptomic and histological analysis of human plaque spanning a range of disease severity and in vitro models of macrophage function was conducted.

RESULTS

Transcriptomic analyses identified a subpopulation of macrophages that expressed the hematopoietic transcription factor GATA2. These GATA2-expressing macrophages had a transcriptional profile that was intermediary between monocytes and mature macrophages and selectively upregulated genes associated with proliferation and apoptosis. The expression of GATA2 was concomitant with plaque macrophage proliferation at all stages of disease but not macrophage proliferation in other tissues, with >90% of proliferating atheroma macrophages expressing GATA2. GATA2 was upregulated in macrophages following exposure to oxidized low-density lipoprotein, with GATA2 expression being necessary and sufficient for the proliferation of these macrophages. In these cells, GATA2 mediates proliferation by upregulating expression of the protooncogene MYB, while simultaneously decreasing sensitivity to apoptosis induced by the unfolded protein response.

CONCLUSIONS

Together, these data identify GATA2 as a transcription factor upregulated by atherogenic stimuli that functions as the primary mediator of macrophage proliferation in atherosclerotic plaque.