Bone marrow angiotensin AT2 receptor deficiency aggravates atherosclerosis development by eliminating macrophage liver X receptor-mediated anti-atherogenic actions

Abstract

Background: Bone marrow (BM) Angiotensin II (Ang II) type 1 (AT1) receptor plays a crucial role in atherosclerosis development; however, the effect of BM Ang II type 2 (AT2) receptor on atherogenesis remains undefined. Methods and results: We generated BM chimera apoE-deficient (apoE-/-) mice whose BM cells were repopulated with AT2-deficient (Agtr2-/-) or wild-type (Agtr2+/+) cells. After 2 months of a high-cholesterol diet, the atherosclerotic lesion area was significantly increased in the apoE-/-/BM-Agtr2-/- mice compared with the apoE-/-/BM-Agtr2+/+ mice (51%, P < 0.05), accompanied by an augmented accumulation of lesion macrophages. Although phenotypic polarization in BM-derived macrophages and lipopolysaccharide-induced expression of proinflammatory cytokines in thioglycollate-induced peritoneal macrophages (TGPMs) were not affected by AT2-deficiency, mRNA and protein expression levels of macrophage liver X receptor β (LXRβ) were significantly decreased in Agtr2-/- TGPMs compared with Agtr2+/+ TGPMs. Anti-inflammatory effects of LXR agonist (GW3965) were markedly inhibited in Agtr2-/- TGPMs. Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7 were much lower in Agtr2-/- TGPMs than Agtr2+/+ TGPMs, accompanied by a significantly reduced cholesterol efflux. Conclusions: Our findings demonstrate that BM-AT2 deficiency aggravates atherosclerosis, at least in part, by eliminating the anti-atherogenic properties of macrophages elicited by LXRβ activation.