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.V.
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
N1 - Publisher Copyright:
© 2020 The Authors.
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
UR - http://www.scopus.com/inward/record.url?scp=85084746808&partnerID=8YFLogxK
U2 - 10.1161/CIRCRESAHA.119.316206
DO - 10.1161/CIRCRESAHA.119.316206
M3 - Review article
C2 - 32160811
AN - SCOPUS:85084746808
SN - 0009-7330
VL - 126
SP - 1346
EP - 1359
JO - Circulation research
JF - Circulation research
IS - 10
ER -