Abstract 12460: Deletion of the Angiotensin II Type 1a Receptor Prevents Atherosclerotic Plaque Rupture
Background: Atherosclerotic plaque rupture and subsequent thrombus formation can trigger acute coronary syndrome. Angiotensin II, a principal vasoactive substance of the renin-angiotensin system, is involved in the genesis of atherosclerosis. However, since the role of the angiotensin II type 1a receptor (AT1aR) in plaque rupture is poorly understood, we assessed the hypothesis that AT1aR contributes to atherosclerotic plaque rupture.
Methods and Results: Atherosclerotic plaque rupture was induced in apolipoprotein E (ApoE) knockout and ApoE/AT1aR double knockout mice by carotid artery ligation for 4 weeks, followed by polyethylene cuff placement. The incidence of plaque rupture at 4 days after cuff placement was significantly reduced in ApoE/AT1aR double knockout (23.8%, n=21) compared with ApoE knockout mice (72.0%, n=25) (P<0.01). Lipid accumulation, macrophage infiltration and superoxide anion production in atherosclerotic plaque were markedly attenuated in ApoE/AT1aR knockout compared with ApoE knockout mice. AT1aR deficiency significantly enhanced mRNA expression of ATP-binding cassette transporter A1 in the carotid artery. In contrast, AT1aR deficiency significantly attenuated mRNA expression of monocyte/macrophage-colony stimulating factor, lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and inflammatory cytokines. Moreover, in situ gelatin zymography revealed that matrix metalloproteinase activity was markedly reduced in ApoE/AT1aR double knockout compared with ApoE knockout mice. Studies in cultured mouse peritoneal macrophages showed that AT1aR deficiency limited lipopolysaccharide-induced LOX-1 mRNA expression, inflammatory cytokines and matrix metalloproteinase. Furthermore, a phagocytosis assay using IgG opsonized sheep red blood cells showed that AT1aR deficiency significantly reduced the phagocytic capability of macrophages.
Conclusions: These results suggest that blocking AT1aR might decrease atherosclerotic plaque rupture and that AT1aR-mediated inflammation, oxidative stress and MMP activation may play important roles in plaque vulnerability.
- © 2010 by American Heart Association, Inc.