Hofmann Anja, Brunssen Coy, Poitz David M, Langbein Heike, Strasser Ruth H, Henle Thomas, Ravens Ursula, Morawietz Henning
Division of Vascular Endothelium and Microcirculation, Department of Medicine III, University Hospital and Medical Faculty Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany.
Department of Internal Medicine and Cardiology at the Technische Universität Dresden, Dresden, Germany.
Atheroscler Suppl. 2017 Nov;30:294-302. doi: 10.1016/j.atherosclerosissup.2017.05.020.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the major receptor for oxidized LDL in endothelial cells. LOX-1 is highly expressed in atherosclerotic plaques. The impact of LOX-1 on development of endothelial dysfunction in large vessels in absence or presence of atherosclerosis-prone conditions has not been studied to date.
Mice with endothelial cell-specific LOX-1 overexpression (bLOX-1tg) were analyzed. Wild-type (WT) mice served as controls. In addition, bLOX-1tg mice were crossed with LDL receptor knockout (Ldlr) mice. All mice were fed a western-type diet (WD) or control diet (CD) for 20 weeks. Afterwards, endothelial function was analyzed ex vivo in thoracic aortas using a Mulvany myograph.
WD induced hypertriglyceridemia (bLOX-1tg: 1.6-fold; WT: 1.4-fold) and hypercholesterolemia (P < 0.0001) in bLOX-1tg and WT mice without HDL-elevation in bLOX-1tg mice. Gonadal fat pad weight was 1.7 and 1.2-fold increased on CD and WD in bLOX-1tg mice compared to WT. LOX-1 overexpression impaired endothelial function by 15-16% (P < 0.05) on CD and WD. Crossing bLOX-1tg mice into Ldlr background strongly elevated total (∼6-fold) and LDL-cholesterol (∼9-fold) compared to WT and bLOX-1tg mice on WD. Endothelial function in response to WD was impaired in bLOX-1tg/Ldlr mice (Eff: 56.7 ± 23.0%) compared to WT (Eff: 88.2 ± 15.8%, P < 0.001), bLOX-1tg (Eff: 76.7 ± 12.9%, P < 0.05) and Ldlr mice (Eff: 70.1 ± 13.1%, P < 0.05). No differences between WT, bLOX-1tg and Ldlr mice were detectable when comparing all genotypes.
Endothelial LOX-1 overexpression in an atherosclerosis-prone background impairs endothelial function, proving its importance in the development of atherosclerosis.
凝集素样氧化低密度脂蛋白受体1（LOX-1）是内皮细胞中氧化型低密度脂蛋白的主要受体。LOX-1在动脉粥样硬化斑块中高表达。迄今为止，尚未研究在存在或不存在动脉粥样硬化易患条件下，LOX-1对大血管内皮功能障碍发展的影响。
分析了内皮细胞特异性LOX-1过表达的小鼠（bLOX-1tg）。野生型（WT）小鼠作为对照。此外，将bLOX-1tg小鼠与低密度脂蛋白受体敲除（Ldlr）小鼠杂交。所有小鼠均喂食西式饮食（WD）或对照饮食（CD）20周。之后，使用Mulvany肌动描记器在体外用胸主动脉分析内皮功能。
WD在bLOX-1tg和WT小鼠中诱导了高甘油三酯血症（bLOX-1tg：1.6倍；WT：1.4倍）和高胆固醇血症（P < 0.0001），且bLOX-1tg小鼠中高密度脂蛋白未升高。与WT相比，bLOX-1tg小鼠在CD和WD上性腺脂肪垫重量分别增加了1.7倍和1.2倍。在CD和WD上，LOX-1过表达使内皮功能受损15 - 16%（P < 0.05）。与WD上的WT（Eff：88.2 ± 15.8%）、bLOX-1tg（Eff：76.7 ± 12.9%，P < 0.05）和Ldlr小鼠（Eff：70.1 ± 13.1%，P < 0.05）相比，bLOX-1tg/Ldlr小鼠对WD的内皮功能受损（Eff：56.7 ± 23.0%）。比较所有基因型时，WT、bLOX-1tg和Ldlr小鼠之间未检测到差异。
在动脉粥样硬化易患背景下内皮LOX-1过表达会损害内皮功能，证明其在动脉粥样硬化发展中的重要性。
