LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet
LOX-1 deletion decreases collagen accumulation in atherosclerotic plaque in low-density lipoprotein receptor knockout mice fed a high-cholesterol diet
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DOI：
10.1093/cvr/cvn110
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发表时间：
2008-07-15
影响因子：
10.8
通讯作者：
Mehta, Jawahar L.
中科院分区：
文献类型：
--
作者：
Hu, Changping;Dandapat, Abhijit;Mehta, Jawahar L.
胶原蛋白作为细胞外基质的一种成分，与动脉粥样硬化斑块的形成和稳定性有关。LOX-1是一种凝集素样氧化低密度脂蛋白（LDL）受体-1，其活化在胶原形成中发挥重要作用。我们研究的假设，LOX-1缺失可能会抑制胶原蛋白的积累在动脉粥样硬化动脉中的LDL受体（LDLR）敲除（KO）migration.Methods和结果我们产生LOX-1 KO和LOX-1/LDLR双KO小鼠的C57 BL/6（野生型小鼠）的背景和喂养4%胆固醇/10%可可脂饮食18周。在LDLR KO小鼠中，血管壁胶原积累增加与动脉粥样硬化形成相关（与野生型小鼠相比P < 0.01），但在双KO小鼠中则少得多（与LDLR KO小鼠相比P < 0.01）。胶原蛋白蓄积数据与前胶原蛋白I测量结果相证实。骨桥蛋白、纤连蛋白和基质金属蛋白酶（MMP-2和MMP-9）的表达/活性在LDLR KO小鼠中也增加（与野生型小鼠相比P < 0.01），但在LOX-1缺失的小鼠中没有增加（与LDLR KO小鼠相比P < 0.01）。NADPH氧化酶（p47（phox）、p22（phox）、gp 91（phox）和Nox-4亚基）和硝基酪氨酸的表达在LDLR KO小鼠中增加（与野生型小鼠相比P < 0.01），而在LOX-1缺失小鼠中没有增加（与LDLR KO小鼠相比P < 0.01）。结论LOX-1基因敲除可抑制动脉粥样硬化区胶原沉积和MMP的表达，其机制可能与LOX-1基因敲除抑制促氧化信号有关。
Aims Collagen, as a component of the extracellular matrix, has been linked to atherosclerotic plaque formation and stability. Activation of LOX-1, a lectin-like oxidized low-density lipoprotein (LDL) receptor-1, exerts a significant role in collagen formation. We examine the hypothesis that LOX-1 deletion may inhibit collagen accumulation in atherosclerotic arteries in LDL receptor (LDLR) knockout (KO) mice.Methods and results We generated LOX-1 KO and LOX-1/LDLR double KO mice on a C57BL/6 (wild-type mice) background and fed a 4% cholesterol/10% cocoa butter diet for 18 weeks. Vessel wall collagen accumulation was increased in association with atherogenesis in the LDLR KO mice ( P < 0.01 vs. wildtype mice), but much less so in the double KO mice ( P < 0.01 vs. LDLR KO mice). Collagen accumulation data were corroborated with pro-collagen I measurements. Expression/activity of osteopontin, fibronectin, and matrix metalloproteinases ( MMP-2 and MMP-9) was also increased in the LDLR KO mice ( P < 0.01 vs. wild-type mice), but not in the mice with LOX-1 deletion ( P < 0.01 vs. LDLR KO mice). The expression of NADPH oxidase ( p47(phox), p22(phox), gp91(phox), and Nox-4 subunits) and nitrotyrosine was increased in the LDLR KO mice ( P < 0.01 vs. wild-type mice) and not in mice with LOX-1 deletion ( P < 0.01 vs. LDLR KO mice). Phosphorylation of Akt-1 and endothelial nitric oxide synthase and expression of haem-oxygenase-1 were found to be reduced in the LDLR KO mice ( P < 0.01 vs. wildtype mice), but not in the mice with LOX-1 deletion ( P < 0.01 vs. LDLR KO mice).Conclusion LOX-1 deletion reduces enhanced collagen deposition and MMP expression in atherosclerotic regions via inhibition of pro-oxidant signals.