脂蛋白(a)上的氧化磷脂引发人体动脉壁炎症和炎性单核细胞反应。
Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans.
作者信息
van der Valk Fleur M, Bekkering Siroon, Kroon Jeffrey, Yeang Calvin, Van den Bossche Jan, van Buul Jaap D, Ravandi Amir, Nederveen Aart J, Verberne Hein J, Scipione Corey, Nieuwdorp Max, Joosten Leo A B, Netea Mihai G, Koschinsky Marlys L, Witztum Joseph L, Tsimikas Sotirios, Riksen Niels P, Stroes Erik S G
机构信息
From Department of Vascular Medicine (F.M.V.d.V., M.N., E.S.G.S.), Department of Molecular Cell Biology, Sanquin Research (J.K., J.D.v.B.), Experimental Vascular Biology, (J.v.d.B.), Department of Radiology (A.J.N.), and Department of Nuclear Medicine (H.J.V.), Academic Medical Center, Amsterdam, the Netherlands; Departments of Internal Medicine (S.B., L.A.B.J., M.G.N., N.P.R.) and Pharmacology-Toxicology (N.P.R.), Radboud UMC, Nijmegen, the Netherlands; Sulpizio Cardiovascular Center, Division of Cardiovascular Medicine (C.Y., S.T.) and Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University California, San Diego, La Jolla; St. Boniface Hospital Research Centre, University of Manitoba, Winnipeg, Canada (A.R.); Department of Chemistry, Biochemistry and Pharmacology, University of Windsor, Windsor, Canada (C.S.); and Robarts Research Institute, Schulich School of Medicine, Western University, London, Canada (M.L.K.).
出版信息
Circulation. 2016 Aug 23;134(8):611-24. doi: 10.1161/CIRCULATIONAHA.116.020838. Epub 2016 Aug 5.
BACKGROUND
Elevated lipoprotein(a) [Lp(a)] is a prevalent, independent cardiovascular risk factor, but the underlying mechanisms responsible for its pathogenicity are poorly defined. Because Lp(a) is the prominent carrier of proinflammatory oxidized phospholipids (OxPLs), part of its atherothrombosis might be mediated through this pathway.
METHODS
In vivo imaging techniques including magnetic resonance imaging, (18)F-fluorodeoxyglucose uptake positron emission tomography/computed tomography and single-photon emission computed tomography/computed tomography were used to measure subsequently atherosclerotic burden, arterial wall inflammation, and monocyte trafficking to the arterial wall. Ex vivo analysis of monocytes was performed with fluorescence-activated cell sorter analysis, inflammatory stimulation assays, and transendothelial migration assays. In vitro studies of the pathophysiology of Lp(a) on monocytes were performed with an in vitro model for trained immunity.
RESULTS
We show that subjects with elevated Lp(a) (108 mg/dL [50-195 mg/dL]; n=30) have increased arterial inflammation and enhanced peripheral blood mononuclear cells trafficking to the arterial wall compared with subjects with normal Lp(a) (7 mg/dL [2-28 mg/dL]; n=30). In addition, monocytes isolated from subjects with elevated Lp(a) remain in a long-lasting primed state, as evidenced by an increased capacity to transmigrate and produce proinflammatory cytokines on stimulation (n=15). In vitro studies show that Lp(a) contains OxPL and augments the proinflammatory response in monocytes derived from healthy control subjects (n=6). This effect was markedly attenuated by inactivating OxPL on Lp(a) or removing OxPL on apolipoprotein(a).
CONCLUSIONS
These findings demonstrate that Lp(a) induces monocyte trafficking to the arterial wall and mediates proinflammatory responses through its OxPL content. These findings provide a novel mechanism by which Lp(a) mediates cardiovascular disease.
CLINICAL TRIAL REGISTRATION
URL: http://www.trialregister.nl. Unique identifier: NTR5006 (VIPER Study).
背景
脂蛋白(a)[Lp(a)]升高是一种常见的独立心血管危险因素，但其致病的潜在机制尚不清楚。由于Lp(a)是促炎氧化磷脂(OxPLs)的主要载体，其动脉粥样硬化血栓形成的部分机制可能通过该途径介导。
方法
采用包括磁共振成像、(18)F-氟脱氧葡萄糖摄取正电子发射断层扫描/计算机断层扫描和单光子发射计算机断层扫描/计算机断层扫描在内的体内成像技术，依次测量动脉粥样硬化负担、动脉壁炎症和单核细胞向动脉壁的迁移。采用荧光激活细胞分选分析、炎症刺激试验和跨内皮迁移试验对单核细胞进行体外分析。利用训练免疫体外模型对Lp(a)对单核细胞的病理生理学进行体外研究。
结果
我们发现，与Lp(a)正常的受试者(7mg/dL[2-28mg/dL]；n=30)相比，Lp(a)升高的受试者(108mg/dL[50-195mg/dL]；n=30)动脉炎症增加，外周血单核细胞向动脉壁的迁移增强。此外，从Lp(a)升高的受试者中分离出的单核细胞保持长期的预激活状态，刺激后迁移和产生促炎细胞因子的能力增加证明了这一点(n=15)。体外研究表明，Lp(a)含有OxPL，并增强了健康对照受试者来源的单核细胞中的促炎反应(n=6)。通过使Lp(a)上的OxPL失活或去除载脂蛋白(a)上的OxPL，这种效应明显减弱。
结论
这些发现表明，Lp(a)诱导单核细胞向动脉壁迁移，并通过其OxPL含量介导促炎反应。这些发现为Lp(a)介导心血管疾病提供了一种新机制。
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