Paradoxical Suppression of Atherosclerosis in the Absence of microRNA-146a

Rationale: Inflammation is a key contributor to atherosclerosis. MicroRNA-146a (miR-146a) has been identified as a critical brake on pro-inflammatory NF-κB signalling in several cell types, including endothelial cells and bone marrow-derived cells. Importantly, miR-146a expression is elevated in human atherosclerotic plaques, and polymorphisms in the miR-146a pre-cursor have been associated with risk of coronary artery disease. Objective: To define the role of endogenous miR-146a during atherogenesis. Methods and Results: Paradoxically, Low-density lipoprotein receptor ( Ldlr) -/- mice deficient in miR-146a develop less atherosclerosis, despite having highly elevated levels of circulating pro-inflammatory cytokines. In contrast, cytokine levels are normalized in Ldlr -/- ;miR-146a -/- mice receiving wild-type bone marrow transplantation, and these mice have enhanced endothelial cell activation and elevated atherosclerotic plaque burden compared to Ldlr -/- mice receiving wild-type bone marrow; demonstrating the atheroprotective role of miR-146a in the endothelium. We find that deficiency of miR-146a in bone marrow-derived cells precipitates defects in hematopoietic stem cell function, contributing to extramedullary hematopoiesis, splenomegaly, bone marrow failure and decreased levels of circulating pro-atherogenic cells in mice fed an atherogenic diet. These hematopoietic phenotypes appear to be driven by unrestrained inflammatory signalling that leads to the expansion and eventual exhaustion of hematopoietic cells, and this occurs in the face of lower levels of circulating LDL cholesterol in mice lacking miR-146a in bone marrow-derived cells. Furthermore, we identify Sort1 , a known regulator of circulating LDL levels in humans, as a novel target of miR-146a. Conclusions: Our study reveals that miR-146a regulates cholesterol metabolism and tempers chronic inflammatory responses to atherogenic diet by restraining pro-inflammatory signalling in endothelial cells and bone marrow-derived cells.