Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation

Author:

Schnitzler Johan G.1,Hoogeveen Renate M.2,Ali Lubna1,Prange Koen H.M.3,Waissi Farahnaz45,van Weeghel Michel67,Bachmann Julian C.1,Versloot Miranda1,Borrelli Matthew J.8,Yeang Calvin9,De Kleijn Dominique P.V.410,Houtkooper Riekelt H.6,Koschinsky Marlys L.8,de Winther Menno P.J.311,Groen Albert K.112,Witztum Joseph L.13,Tsimikas Sotirios9,Stroes Erik S.G.2,Kroon Jeffrey1ORCID

Affiliation:

1. From the Experimental Vascular Medicine (J.G.S., L.A., J.C.B., M.V., A.K.G., J.K.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands

2. Vascular Medicine (R.M.H., E.S.G.S.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands

3. Medical Biochemistry (K.H.M.P., M.P.J.d.W.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands

4. Vascular Surgery, Netherlands (F.W., D.P.V.D.K.), UMC Utrecht, University Utrecht, the Netherlands

5. Cardiology (F.W.), UMC Utrecht, University Utrecht, the Netherlands

6. Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology and Metabolism (M.v.W., R.H.H.), Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, the Netherlands

7. Core Facility Metabolomics, Amsterdam UMC, University of Amsterdam, the Netherlands (M.v.W.)

8. Robarts Research Institute, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Canada (M.J.B., M.L.K.)

9. Vascular Medicine Program, Division of Cardiology, Department of Medicine, Sulpizio Cardiovascular Center (C.Y., S.T.), University of California San Diego, La Jolla

10. Netherlands Heart Institute (D.P.V.D.K.), UMC Utrecht, University Utrecht, the Netherlands

11. Institute for Cardiovascular Prevention, Munich, Germany (M.P.J.d.W.)

12. Pediatrics, Laboratory of Metabolic Diseases, University of Groningen, University Medical Center Groningen, the Netherlands (A.K.G.).

13. Division of Endocrinology and Metabolism, Department of Medicine (J.L.W.), University of California San Diego, La Jolla

Abstract

Rationale: Patients with elevated levels of lipoprotein(a) [Lp(a)] are hallmarked by increased metabolic activity in the arterial wall on positron emission tomography/computed tomography, indicative of a proinflammatory state. Objective: We hypothesized that Lp(a) induces endothelial cell inflammation by rewiring endothelial metabolism. Methods and Results: We evaluated the impact of Lp(a) on the endothelium and describe that Lp(a), through its oxidized phospholipid content, activates arterial endothelial cells, facilitating increased transendothelial migration of monocytes. Transcriptome analysis of Lp(a)-stimulated human arterial endothelial cells revealed upregulation of inflammatory pathways comprising monocyte adhesion and migration, coinciding with increased 6-phophofructo-2-kinase/fructose-2,6-biphosphatase (PFKFB)-3–mediated glycolysis. ICAM (intercellular adhesion molecule)-1 and PFKFB3 were also found to be upregulated in carotid plaques of patients with elevated levels of Lp(a). Inhibition of PFKFB3 abolished the inflammatory signature with concomitant attenuation of transendothelial migration. Conclusions: Collectively, our findings show that Lp(a) activates the endothelium by enhancing PFKFB3-mediated glycolysis, leading to a proadhesive state, which can be reversed by inhibition of glycolysis. These findings pave the way for therapeutic agents targeting metabolism aimed at reducing inflammation in patients with cardiovascular disease.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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