title: The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease.
abstract: Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shirai
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Nazarewicz
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Wallis
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Rolando E
authors.initials: RE
authors.lastname: Yanes
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Ryu
authors.initials: R
authors.lastname: Watanabe
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Marc
authors.initials: M
authors.lastname: Hilhorst
authors.affiliation: Division of Biostatistics, Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Lu
authors.initials: L
authors.lastname: Tian
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232.
authors.forename: David G
authors.initials: DG
authors.lastname: Harrison
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: John C
authors.initials: JC
authors.lastname: Giacomini
authors.affiliation: Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Themistocles L
authors.initials: TL
authors.lastname: Assimes
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305.
authors.forename: Jörg J
authors.initials: JJ
authors.lastname: Goronzy
authors.affiliation: Division of Immunology and Rheumatology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305 cweyand@stanford.edu.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Weyand
mesh_terms: D000368:Aged; D019069:Cell Respiration; D003324:Coronary Artery Disease / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D006801:Humans; D007249:Inflammation / Q000473:pathology*; D053583:Interleukin-1beta / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D010766:Phosphorylation; D055503:Protein Multimerization; D011770:Pyruvate Kinase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D053583:Interleukin-1beta; D015850:Interleukin-6; D017382:Reactive Oxygen Species; D050796:STAT3 Transcription Factor; D011770:Pyruvate Kinase; D005947:Glucose