Abstract 528: Bone Marrow Angiotensin AT2 Receptor Deficiency Aggravates Atherosclerosis by Eliminating Macrophage Liver X Receptor-Mediated Antiatherogenic Actions
[BACKGROUND] The angiotensin II (Ang II) type 2 (AT2) receptor is crucially involved in atherogenesis; however, bone marrow (BM) AT2-mediated anti-atherogenic action remains undefined.
[METHOD AND RESULT] We generated BM chimera apoE-deficient (apoE-/-) mice whose BM cells were repopulated with AT2-deficient (Agtr2-/-) or wild type (Agtr2+/+) cells. Eight weeks after BM transplantation, all mice were fed a western diet for two months. Atherosclerotic lesion area was significantly increased in apoE-/-/BM-Agtr2-/- mice compared with apoE-/-/BM-Agtr2+/+ mice (51%, P<0.05), accompanied by the enhanced accumulation of MOMA-2 positive cells (P<0.05). Hemodynamic data and lipid profile did not differ between the two groups. We first examined the expression levels of macrophage liver X receptors (LXRα and β), which have been reported to exert anti-atherogenic actions by reducing pro-inflammatory response and promoting cholesterol efflux and macrophage emigration. The mRNA expression of LXRβ, but not LXRα, was significantly decreased by 21% in Agtr2-/- thioglycollate-induced peritoneal macrophages (TGPM) compared with Agtr2+/+ TGPM (P<0.01). Inversely, LXRβ mRNA expression was markedly increased by co-treatment of angiotensin II (100nM) with AT1 receptor blocker, Olmesartan (10μM) (47%, p<0.01). Treatment with LXR agonist (GW3965) significantly attenuated LPS-induced mRNA expressions of TNF-α and IL-1β in Agtr2+/+ TGPM (35%, 46%, respectively, P<0.01), however, anti-inflammatory effect of LXR agonist was markedly reduced in Agtr2-/- TGPM (p<0.05). Furthermore, the expression levels of ATP-binding cassette transporter ABCA1 and CCR7, essentially implicated in cholesterol efflux and macrophage emigration, were much lower in Agtr2-/- TGPM than Agtr2+/+ TGPM (34%, 53%, p<0.01). Flow cytometric analysis also showed a significantly lower expression of CCR7 in Agtr2-/- TGPM (24%, p<0.05).
[CONCLUSION] Our findings demonstrate that BM-AT2 deficiency aggravates atherosclerosis, at least in part, by eliminating anti-atherogenic properties elicited by macrophage LXR activation, suggesting that AT2-mediated regulation of macrophage LXR activity could be a novel therapeutic target for the prevention of atherosclerosis.
- © 2012 by American Heart Association, Inc.