Abstract
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1-6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.
Highlights
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and was studied
The present study demonstrates the role of PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation and deciphers the underlying mechanisms
The effect of Ox-LDL on the PKM2 pathway was dose dependent because significant increases in PKM2 expression, PKM2 tyrosine 105 phosphorylation, and interleukin 1 (IL-1) mRNA and protein expression were observed with increasing doses of Ox-LDL
Summary
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and was studied. This study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.—Kumar, A., P. Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation. In LPS-activated macrophages and cancerous cells, the monomer or dimer form of PKM2 translocates to the nucleus where it interacts with hypoxia-inducible factor-1 (Hif-1 ) and induces expression of pro-inflammatory cytokine IL-1 and pro-glycolytic enzymes [15, 16]. Macrophage foam cell formation can be regulated at several levels, such as lipid uptake, biosynthesis, and efflux [18]
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