Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet
Deletion of LOX-1 reduces atherogenesis in LDLR knockout mice fed high cholesterol diet
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DOI：
10.1161/circresaha.107.149724
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发表时间：
2007-06-08
影响因子：
20.1
通讯作者：
Sawamura, Tatsuya
中科院分区：
文献类型：
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作者：
Mehta, Jawahar L.;Sanada, Nobuhito;Sawamura, Tatsuya
动脉粥样硬化与氧化应激和炎症以及LOX-1（氧化LDL（oxLDL）的内皮受体）的上调相关。在这里，我们描述了LOX-1基因敲除（KO）小鼠的产生，其中oxLDL与主动脉内皮的结合减少，并且在用oxLDL治疗后保持内皮依赖性血管舒张（与野生型小鼠相比P < 0.01）。为了解决内皮功能保留是否可能导致动脉粥样硬化形成减少，我们将LOX-1 KO小鼠与LDLR KO小鼠杂交，并给这些小鼠喂食4%胆固醇/ 10%可可脂饮食18周。在LDLR KO小鼠中发现动脉粥样硬化覆盖61 +/-2%的主动脉，但在双KO小鼠中仅覆盖36 +/-3%的主动脉。双KO小鼠（与LDLR KO小鼠相比）的管腔阻塞和内膜厚度显著降低。在LDLR KO小鼠中，氧化还原敏感性NF-κ B和炎性标志物CD 68的表达增加（与野生型小鼠相比P < 0.01），但在双KO小鼠中没有增加。另一方面，在LDLR KO小鼠中，TNF-α细胞因子IL-10表达和超氧化物歧化酶活性较低（与野生型小鼠相比P < 0.01），但在双KO小鼠中并非如此。内皮型一氧化氮合酶的表达也保留在双基因敲除小鼠。LDLR KO小鼠中促炎信号MAPK P38被激活，而LOX-1缺失降低了该信号。总之，LOX-1缺失维持内皮功能，导致与促炎和促氧化信号减少相关的动脉粥样硬化形成减少。
Atherosclerosis is associated with oxidative stress and inflammation, and upregulation of LOX-1, an endothelial receptor for oxidized LDL (oxLDL). Here, we describe generation of LOX-1 knockout (KO) mice in which binding of oxLDL to aortic endothelium was reduced and endothelium-dependent vasorelaxation preserved after treatment with oxLDL (P < 0.01 versus wild-type mice). To address whether endothelial functional preservation might lead to reduction in atherogenesis, we crossed LOX-1 KO mice with LDLR KO mice and fed these mice 4% cholesterol/ 10% cocoa butter diet for 18 weeks. Atherosclerosis was found to cover 61 +/- 2% of aorta in the LDLR KO mice, but only 36 +/- 3% of aorta in the double KO mice. Luminal obstruction and intima thickness were significantly reduced in the double KO mice (versus LDLR KO mice). Expression of redox-sensitive NF-kappa B and the inflammatory marker CD68 in LDLR KO mice was increased (P < 0.01 versus wild-type mice), but not in the double KO mice. On the other hand, antiinflammatory cytokine IL-10 expression and superoxide dismutase activity were low in the LDLR KO mice (P < 0.01 versus wild-type mice), but not in the double KO mice. Endothelial nitric oxide synthase expression was also preserved in the double KO mice. The proinflammatory signal MAPK P38 was activated in the LDLR KO mice, and LOX-1 deletion reduced this signal. In conclusion, LOX-1 deletion sustains endothelial function leading to a reduction in atherogenesis in association with reduction in proinflammatory and prooxidant signals.