Deletion of the angiotensin II type 1a receptor prevents atherosclerotic plaque rupture in apolipoprotein E-/- mice

Jun Aono, Jun Suzuki, Masaru Iwai, Masatsugu Horiuchi, Takayuki Nagai, Kazuhisa Nishimura, Katsuji Inoue, Akiyoshi Ogimoto, Hideki Okayama, Jitsuo Higaki
Arteriosclerosis, Thrombosis, and Vascular Biology 2012, 32 (6): 1453-9

OBJECTIVE: Angiotensin II is involved in the genesis of atherosclerosis. As the role of the angiotensin II type 1a (AT(1a)) receptor in plaque rupture is poorly understood, we assessed the hypothesis that the AT(1a)receptor contributes to atherosclerotic plaque rupture.

METHODS AND RESULTS: Atherosclerotic plaque rupture was induced by carotid artery ligation for 4 weeks followed by polyethylene cuff placement around the carotid in apolipoprotein E (ApoE)(-/-) and ApoE(-/-) AT(1a)(-/-) mice. The incidence of plaque rupture at 4 days after cuff placement was 72% in ApoE(-/-) mice compared with 24% in ApoE(-/-) AT(1a)(-/-) mice (P<0.01). Lipid accumulation, macrophage infiltration, expression of inflammatory cytokines, nicotinamide adenine dinucleotide phosphate-oxidase activity, and matrix metalloproteinase-9 activity in atherosclerotic plaque were markedly attenuated in ApoE(-/-) AT(1a)(-/-) compared with ApoE(-/-) mice. Oxidized low-density lipoprotein inhibited macrophage migration in ApoE(-/-) macrophages. In contrast, oxidized low-density lipoprotein-induced macrophage trapping was abolished in ApoE(-/-) AT(1a)(-/-) macrophages, and this was associated with decreased CD36 expression and focal adhesion kinase activity.

CONCLUSIONS: Conclusion- These results suggest that blocking the AT(1) receptor may reduce atherosclerotic plaque rupture and that AT(1a) receptor-mediated macrophage trapping, inflammation, oxidative stress, and matrix metalloproteinase activation may play crucial roles in plaque vulnerability.

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