Critical role of bone marrow angiotensin II type 1 receptor in the pathogenesis of atherosclerosis in apolipoprotein E deficient mice.

Abstract

OBJECTIVE: It is suggested that the angiotensin II (Ang II)-Ang II type 1 receptor (AT1R) pathway plays a pivotal role in the pathogenesis of atherosclerosis. Recently, bone marrow (BM) cells were reported to express AT1R. Here, we investigated the role of AT1R in BM in the pathogenesis of atherosclerosis. METHODS AND RESULTS: Genetic ablation or pharmacological blockade of AT1R led to a significant reduction and stabilization of atherosclerotic lesions in ApoE-/- mice. To elucidate the role of AT1R in BM, we generated several BM chimeric mice. Ang II promoted atherosclerosis progression in the BM chimeric mice that had AT1aR in BM, regardless of the absence of AT1aR in the recipient vasculature (P<0.05). BM chimeric mice whose BM AT1aR was disrupted showed significantly less atherosclerotic lesions in aorta (P<0.05) and more stable plaque with reduced accumulation of BM-derived cells compared with BM chimeric mice that had AT1aR-positive BM. Most of the BM-derived cells in atheroma were positive for a macrophage marker and expressed matrix metalloproteinase (MMP)-9 and monocyte chemoattractant protein-1. CONCLUSIONS: Our findings suggest that AT1R in BM plays an important role in the pathogenesis of atherosclerosis.