Macrophages are key immune cells found in atherosclerotic plaques and critically shape atherosclerotic disease development. The epigenomic enzyme Histone deacetylase 3 (HDAC3) has a role in regulating the atherosclerotic phenotype of macrophages. In rodents, myeloid HDAC3 deficiency promotes collagen deposition in atherosclerotic lesions and thus induces a stable plaque phenotype. Also, macrophages presented a switch to anti-inflammatory wound healing characteristics and showed improved lipid handling.
The pro-fibrotic phenotype was directly linked to epigenetic regulation of the Tgfb1 locus upon HDAC3 deletion, driving smooth muscle cells to increased collagen production. Moreover, in humans, HDAC3 was the sole HDAC upregulated in ruptured atherosclerotic lesions, HDAC3 associated with inflammatory macrophages, and HDAC3 expression inversely correlated with pro-fibrotic TGFB1 expression. Targeting the macrophage epigenome can improve atherosclerosis outcome and HDAC3 is identified as a potential novel therapeutic target in cardiovascular disease.
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