Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Shitsukawa, Toon, Ehime 7910295, Japan.
Arterioscler Thromb Vasc Biol. 2012 Jun;32(6):1453-9. doi: 10.1161/ATVBAHA.112.249516. Epub 2012 Mar 29.
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.
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.
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.
血管紧张素 II 参与动脉粥样硬化的发生。由于血管紧张素 II 型 1a（AT（1a））受体在斑块破裂中的作用尚未完全清楚，我们评估了这样一个假设，即 AT（1a）受体有助于动脉粥样硬化斑块破裂。
通过结扎颈动脉 4 周并在载脂蛋白 E（ApoE）（-/-）和 ApoE（-/-）AT（1a）（-/-）小鼠的颈动脉周围放置聚乙烯套管来诱导动脉粥样硬化斑块破裂。在套管放置后 4 天，ApoE（-/-）小鼠斑块破裂的发生率为 72%，而 ApoE（-/-）AT（1a）（-/-）小鼠为 24%（P<0.01）。与 ApoE（-/-）小鼠相比，ApoE（-/-）AT（1a）（-/-）小鼠的动脉粥样硬化斑块中的脂质积累、巨噬细胞浸润、炎症细胞因子表达、烟酰胺腺嘌呤二核苷酸磷酸氧化酶活性和基质金属蛋白酶-9 活性明显降低。氧化型低密度脂蛋白抑制 ApoE（-/-）巨噬细胞的迁移。相反，氧化型低密度脂蛋白诱导的巨噬细胞捕获在 ApoE（-/-）AT（1a）（-/-）巨噬细胞中被消除，这与 CD36 表达和粘着斑激酶活性降低有关。
这些结果表明，阻断 AT（1）受体可能减少动脉粥样硬化斑块破裂，而 AT（1a）受体介导的巨噬细胞捕获、炎症、氧化应激和基质金属蛋白酶激活可能在斑块易损性中起关键作用。
