Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans

Fleur M van der Valk; Siroon Bekkering; Jeffrey Kroon; Calvin Yeang; Jan Van den Bossche; Jaap D van Buul; Amir Ravandi; Aart J Nederveen; Hein J Verberne; Corey Scipione; Max Nieuwdorp; Leo A B Joosten; Mihai G Netea; Marlys L Koschinsky; Joseph L Witztum; Sotirios Tsimikas; Niels P Riksen; Erik S G Stroes

doi:10.1161/CIRCULATIONAHA.116.020838

Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans

Circulation. 2016 Aug 23;134(8):611-24. doi: 10.1161/CIRCULATIONAHA.116.020838. Epub 2016 Aug 5.

Authors

Fleur M van der Valk¹, Siroon Bekkering¹, Jeffrey Kroon¹, Calvin Yeang¹, Jan Van den Bossche¹, Jaap D van Buul¹, Amir Ravandi¹, Aart J Nederveen¹, Hein J Verberne¹, Corey Scipione¹, Max Nieuwdorp¹, Leo A B Joosten¹, Mihai G Netea¹, Marlys L Koschinsky¹, Joseph L Witztum¹, Sotirios Tsimikas¹, Niels P Riksen¹, Erik S G Stroes²

Affiliations

¹ 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.).
² 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.). e.s.stroes@amc.uva.nl.

Abstract

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).

Keywords: atherosclerosis; lipoproteins; monocytes.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural

MeSH terms

Adult
Aged
Aorta / diagnostic imaging*
Aorta / metabolism*
Cell Movement / physiology
Cells, Cultured
Female
Humans
Inflammation / diagnostic imaging
Inflammation / metabolism
Inflammation Mediators / metabolism*
Leukocytes, Mononuclear / metabolism*
Lipoprotein(a) / metabolism*
Male
Middle Aged
Phospholipids / metabolism*
Positron Emission Tomography Computed Tomography

Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans

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