Loss of PRMT2 in myeloid cells in normoglycemic mice phenocopies impaired regression of atherosclerosis in diabetic mice

Abstract

Abstract The regression, or resolution, of inflammation in atherosclerotic plaques is impaired in diabetes. However, the factors mediating this effect remain incomplete. We identified protein arginine methyltransferase 2 (PRMT2) as a protein whose expression in macrophages is reduced in hyperglycemia and diabetes. PRMT2 catalyzes arginine methylation to target proteins to modulate gene expression. Because PRMT2 expression is reduced in cells in hyperglycemia, we wanted to determine whether PRMT2 plays a causal role in the impairment of atherosclerosis regression in diabetes. We, therefore, examined the consequence of deleting PRMT2 in myeloid cells during the regression of atherosclerosis in normal and diabetic mice. Remarkably, we found significant impairment of atherosclerosis regression under normoglycemic conditions in mice lacking PRMT2 (Prmt2 −/−) in myeloid cells that mimic the decrease in regression of atherosclerosis in WT mice under diabetic conditions. This was associated with increased plaque macrophage retention, as well as increased apoptosis and necrosis. PRMT2-deficient plaque CD68+ cells under normoglycemic conditions showed increased expression of genes involved in cytokine signaling and inflammation compared to WT cells. Consistently, Prmt2 −/− bone marrow-derived macrophages (BMDMs) showed an increased response of proinflammatory genes to LPS and a decreased response of inflammation resolving genes to IL-4. This increased response to LPS in Prmt2 −/− BMDMs occurs via enhanced NF-kappa B activity. Thus, the loss of PRMT2 is causally linked to impaired atherosclerosis regression via a heightened inflammatory response in macrophages. That PRMT2 expression was lower in myeloid cells in plaques from human subjects with diabetes supports the relevance of our findings to human atherosclerosis.