Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.
Angiotensin type 1 receptor blocker reduces intimal neovascularization and plaque growth in apolipoprotein E-deficient mice.
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DOI：
10.1161/hypertensionaha.110.168385
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发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
Murohara T
中科院分区：
文献类型：
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作者：
Cheng XW;Song H;Sasaki T;Hu L;Inoue A;Bando YK;Shi GP;Kuzuya M;Okumura K;Murohara T
在动脉粥样硬化斑块形成中，肾素-血管紧张素系统和新生血管形成之间的相互作用尚不清楚。我们研究了血管紧张素II 1型受体拮抗剂在载脂蛋白E缺陷（ApoE−/−）小鼠动脉粥样硬化发病机制中的作用，特别关注斑块新生血管。将喂食高脂饲料的ApoE−/−小鼠随机分配至2组中的1组，给予溶媒或奥美沙坦12周。主动脉根部和胸主动脉及腹主动脉斑块面积的定量显示，在所有3个区域中，奥美沙坦均降低了内膜新生血管密度和Toll样受体（TLR）2和TLR 4的mRNA水平。奥美沙坦可增加主动脉根部胶原和弹性蛋白的水平，减少巨噬细胞的水平，降低主动脉根部和胸主动脉根部基质金属蛋白酶（MMP）2的mRNA和活性。主动脉环测定显示，奥美沙坦治疗的Apoe-/-小鼠的血管生成反应明显低于未治疗的Apoe-/-小鼠。与未处理对照组相比，奥美沙坦处理的ApoE−/−小鼠的骨髓源性内皮祖细胞样c-Kit+细胞显示细胞功能明显受损，TLR 2/TLR 4和MMP-2表达降低。MMP-2缺陷减少内膜新生血管密度和动脉粥样硬化病变形成。奥美沙坦和靶向TLR 2的小干扰RNA降低TLR 2的水平，MMP-2 mRNA诱导血管紧张素II在培养的内皮细胞。血管紧张素II 1型受体拮抗剂似乎抑制ApoE−/−小鼠的内膜新生血管形成，部分是通过减少TLR 2/TLR 4介导的炎症作用和MMP活化，从而减少动脉粥样硬化斑块生长并增加斑块不稳定性。
The interactions between the renin-angiotensin system and neovascularization in atherosclerotic plaque development are unclear. We investigated the effects of angiotensin II type 1 receptor antagonism in the pathogenesis of atherosclerosis in apolipoprotein E–deficient (ApoE−/−) mice with a special focus on plaque neovascularization. ApoE−/− mice fed a high-fat diet were randomly assigned to 1 of 2 groups and administered vehicle or olmesartan for 12 weeks. Quantification of plaque areas at the aortic root and in the thoracic and abdominal aorta revealed that, in all 3 of the regions, olmesartan reduced intimal neovessel density and the mRNA levels of toll-like receptor (TLR) 2 and TLR4. Olmesartan increased the levels of collagen and elastin, reduced the level of macrophages in the aortic root, and reduced the mRNA and the activity of matrix metalloproteinase (MMP) 2 in aortic roots and thoracic aortas. Aortic ring assay revealed that olmesartan-treated ApoE−/− mice had a markedly lower angiogenic response than that of untreated ApoE−/− mice. Bone marrow–derived endothelial progenitor cell-like c-Kit+ cells from olmesartan-treated ApoE−/− mice showed marked impairment of cellular functions and lower expression of TLR2/TLR4 and MMP-2 compared with those of untreated controls. MMP-2 deficiency reduced intimal neovessel density and atherosclerotic lesion formation. Olmesartan and small-interfering RNA targeting TLR2 reduced the levels of TLR2, and MMP-2 mRNA induced angiotensin II in cultured endothelial cells. Angiotensin II type 1 receptor antagonism appears to inhibit intimal neovascularization in ApoE−/− mice, partly by reducing TLR2/TLR4-mediated inflammatory action and MMP activation, thus decreasing atherosclerotic plaque growth and increasing plaque instability.