Human Neutrophil Peptide 1 Limits Hypercholesterolemia-induced Atherosclerosis by Increasing Hepatic LDL Clearance.
Human Neutrophil Peptide 1 Limits Hypercholesterolemia-induced Atherosclerosis by Increasing Hepatic LDL Clearance.
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DOI：
10.1016/j.ebiom.2017.01.006
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发表时间：
2017-02
期刊：
影响因子：
11.1
通讯作者：
Soehnlein O
中科院分区：
文献类型：
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作者：
Paulin N;Döring Y;Kooijman S;Blanchet X;Viola JR;de Jong R;Mandl M;Hendrikse J;Schiener M;von Hundelshausen P;Vogt A;Weber C;Bdeir K;Hofmann SM;Rensen PCN;Drechsler M;Soehnlein O
血浆LDL-胆固醇升高已明确被确定为动脉粥样硬化的一个致病风险因素。因此，降低LDL-胆固醇的策略可能具有直接的治疗相关性。在这里，我们研究了人中性粒细胞肽1（HNP 1）在小鼠动脉粥样硬化模型中的作用，并确定其有效的动脉粥样硬化保护作用后，转基因过表达和治疗交付。发现该效应是由于血浆LDL-胆固醇降低。从机制上讲，HNP 1与富含LDL的载脂蛋白结合。这种相互作用通过LDL受体促进肝脏中LDL颗粒的清除。因此，我们在这里确定了一个非冗余的机制，HNP 1允许降低LDL-胆固醇，这是一个可以在治疗上指导降低心血管风险的过程。转基因表达人中性粒细胞肽1（HNP 1）的小鼠表现出较低的血浆VLDL/LDL水平和较小的动脉粥样硬化病变大小。重复HNP 1递送通过减少高胆固醇血症而具有动脉粥样硬化保护作用。HNP 1与LDL中的载脂蛋白结合，并促进肝脏中涉及LDL受体的LDL清除。增加的血浆脂质水平（即高胆固醇血症）是动脉粥样硬化的主要风险因素，动脉粥样硬化是心肌梗死和中风的病理基础。在这里，我们表明，人中性粒细胞肽1（HNP 1，也称为α-防御素），一种通常从活化的中性粒细胞释放的抗菌蛋白，结合血浆脂蛋白内的载脂蛋白，并促进肝脏中血浆脂质的清除。因此，用HNP 1重复注射高胆固醇血症小鼠减少了动脉粥样硬化病变的形成。因此，这项研究提供了一种减少高胆固醇血症的创新策略，从而可能降低心血管风险。
Increases in plasma LDL-cholesterol have unequivocally been established as a causal risk factor for atherosclerosis. Hence, strategies for lowering of LDL-cholesterol may have immediate therapeutic relevance. Here we study the role of human neutrophil peptide 1 (HNP1) in a mouse model of atherosclerosis and identify its potent atheroprotective effect both upon transgenic overexpression and therapeutic delivery. The effect was found to be due to a reduction of plasma LDL-cholesterol. Mechanistically, HNP1 binds to apolipoproteins enriched in LDL. This interaction facilitates clearance of LDL particles in the liver via LDL receptor. Thus, we here identify a non-redundant mechanism by which HNP1 allows for reduction of LDL-cholesterol, a process that may be therapeutically instructed to lower cardiovascular risk. Mice with transgenic expression of human neutrophil peptide 1 (HNP1) exhibit lower plasma VLDL/LDL levels and smaller atherosclerotic lesion sizes. Repetitive HNP1 delivery is atheroprotective by reducing hypercholesterolemia. HNP1 binds to apolipoproteins in LDL and facilitates LDL clearance in the liver involving LDL receptor. Increased plasma lipid levels (i.e. hypercholesterolemia) are a primary risk factor for atherosclerosis, the pathology underlying myocardial infarction and stroke. Here we show that human neutrophil peptide 1 (HNP1, also known as α-defensin), an antimicrobial protein typically released from activated neutrophils, binds to apolipoproteins within plasma lipoproteins and facilitates the clearance of plasma lipids in the liver. As a consequence, repeated injection of hypercholesterolemic mice with HNP1 reduces atherosclerotic lesion formation. Thus, this study provides an innovative strategy to reduce hypercholesterolemia and hence a way to potentially reduce cardiovascular risk.