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

Johan G. Schnitzler; Renate M. Hoogeveen; Lubna Ali; Koen H. M. Prange; Farahnaz Waissi; Michel van Weeghel; Julian C. Bachmann; Miranda Versloot; Matthew J. Borrelli; Calvin Yeang; Dominique P. De Kleijn; Riekelt H. Houtkooper; Marlys L. Koschinsky; Menno P. J. de Winther; Albert K. Groen; Joseph L. Witztum; Sotirios Tsimikas; Erik S. G. Stroes; Jeffrey Kroon

doi:10.1161/CIRCRESAHA.119.316206

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

Johan G. Schnitzler, Renate M. Hoogeveen, Lubna Ali, Koen H. M. Prange, Farahnaz Waissi, Michel van Weeghel, Julian C. Bachmann, Miranda Versloot, Matthew J. Borrelli, Calvin Yeang, Dominique P. De Kleijn, Riekelt H. Houtkooper, Marlys L. Koschinsky, Menno P. J. de Winther, Albert K. Groen, Joseph L. Witztum, Sotirios Tsimikas, Erik S. G. Stroes, Jeffrey Kroon^*

^*Corresponding author for this work

Center for Liver, Digestive and Metabolic Diseases (CLDM)

Research output: Contribution to journal › Article › Academic › peer-review

111 Citations (Scopus)

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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.

Original language	English
Pages (from-to)	1346-1359
Number of pages	14
Journal	Circulation Research
Volume	126
Issue number	10
DOIs	https://doi.org/10.1161/CIRCRESAHA.119.316206
Publication status	Published - 8-May-2020

Keywords

endothelial cell
glycolysis
inflammation
lipoprotein(a)
metabolism
ENDOTHELIAL-CELL METABOLISM
OXIDATION-SPECIFIC EPITOPES
OXIDIZED PHOSPHOLIPIDS
EXPRESSION
APOLIPOPROTEIN(A)
STRESS
ATHEROSCLEROSIS
DYSFUNCTION
MACROPHAGE
MONOCYTES

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Schnitzler, J. G., Hoogeveen, R. M., Ali, L., Prange, K. H. M., Waissi, F., van Weeghel, M., Bachmann, J. C., Versloot, M., Borrelli, M. J., Yeang, C., De Kleijn, D. P., Houtkooper, R. H., Koschinsky, M. L., de Winther, M. P. J., Groen, A. K., Witztum, J. L., Tsimikas, S., Stroes, E. S. G., & Kroon, J. (2020). Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation. Circulation Research, 126(10), 1346-1359. https://doi.org/10.1161/CIRCRESAHA.119.316206

@article{3007c20249bb470081eb5d6127a2a03c,

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

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.",

keywords = "endothelial cell, glycolysis, inflammation, lipoprotein(a), metabolism, ENDOTHELIAL-CELL METABOLISM, OXIDATION-SPECIFIC EPITOPES, OXIDIZED PHOSPHOLIPIDS, EXPRESSION, APOLIPOPROTEIN(A), STRESS, ATHEROSCLEROSIS, DYSFUNCTION, MACROPHAGE, MONOCYTES",

author = "Schnitzler, {Johan G.} and Hoogeveen, {Renate M.} and Lubna Ali and Prange, {Koen H. M.} and Farahnaz Waissi and {van Weeghel}, Michel and Bachmann, {Julian C.} and Miranda Versloot and Borrelli, {Matthew J.} and Calvin Yeang and {De Kleijn}, {Dominique P.} and Houtkooper, {Riekelt H.} and Koschinsky, {Marlys L.} and {de Winther}, {Menno P. J.} and Groen, {Albert K.} and Witztum, {Joseph L.} and Sotirios Tsimikas and Stroes, {Erik S. G.} and Jeffrey Kroon",

year = "2020",

month = may,

day = "8",

doi = "10.1161/CIRCRESAHA.119.316206",

language = "English",

volume = "126",

pages = "1346--1359",

journal = "Circulation Research",

issn = "0009-7330",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "10",

}

Schnitzler, JG, Hoogeveen, RM, Ali, L, Prange, KHM, Waissi, F, van Weeghel, M, Bachmann, JC, Versloot, M, Borrelli, MJ, Yeang, C, De Kleijn, DP, Houtkooper, RH, Koschinsky, ML, de Winther, MPJ, Groen, AK, Witztum, JL, Tsimikas, S, Stroes, ESG & Kroon, J 2020, 'Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation', Circulation Research, vol. 126, no. 10, pp. 1346-1359. https://doi.org/10.1161/CIRCRESAHA.119.316206

TY - JOUR

T1 - Atherogenic Lipoprotein(a) Increases Vascular Glycolysis, Thereby Facilitating Inflammation and Leukocyte Extravasation

AU - Schnitzler, Johan G.

AU - Hoogeveen, Renate M.

AU - Ali, Lubna

AU - Prange, Koen H. M.

AU - Waissi, Farahnaz

AU - van Weeghel, Michel

AU - Bachmann, Julian C.

AU - Versloot, Miranda

AU - Borrelli, Matthew J.

AU - Yeang, Calvin

AU - De Kleijn, Dominique P.

AU - Houtkooper, Riekelt H.

AU - Koschinsky, Marlys L.

AU - de Winther, Menno P. J.

AU - Groen, Albert K.

AU - Witztum, Joseph L.

AU - Tsimikas, Sotirios

AU - Stroes, Erik S. G.

AU - Kroon, Jeffrey

PY - 2020/5/8

Y1 - 2020/5/8

N2 - 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.

AB - 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.

KW - endothelial cell

KW - glycolysis

KW - inflammation

KW - lipoprotein(a)

KW - metabolism

KW - ENDOTHELIAL-CELL METABOLISM

KW - OXIDATION-SPECIFIC EPITOPES

KW - OXIDIZED PHOSPHOLIPIDS

KW - EXPRESSION

KW - APOLIPOPROTEIN(A)

KW - STRESS

KW - ATHEROSCLEROSIS

KW - DYSFUNCTION

KW - MACROPHAGE

KW - MONOCYTES

U2 - 10.1161/CIRCRESAHA.119.316206

DO - 10.1161/CIRCRESAHA.119.316206

M3 - Article

SN - 0009-7330

VL - 126

SP - 1346

EP - 1359

JO - Circulation Research

JF - Circulation Research

IS - 10

ER -

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

Abstract

Keywords

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