title: Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis.
abstract: OBJECTIVE
  Small-molecule hypoxia-inducible factor prolyl 4-hydroxylase (HIF-P4H) inhibitors are being explored in clinical studies for the treatment of anemia. HIF-P4H-2 (also known as PHD2 or EglN1) inhibition improves glucose and lipid metabolism and protects against obesity and metabolic dysfunction. We studied here whether HIF-P4H-2 inhibition could also protect against atherosclerosis.
  
  
  RESULTS
  Atherosclerosis development was studied in low-density lipoprotein (LDL) receptor-deficient mice treated with an oral HIF-P4H inhibitor, FG-4497, and in HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice, all mice being fed a high-fat diet. FG-4497 administration to LDL receptor-deficient mice reduced the area of atherosclerotic plaques by ≈50% when compared with vehicle-treated controls and also reduced their weight gain, insulin resistance, liver and white adipose tissue (WAT) weights, adipocyte size, number of inflammation-associated WAT macrophage aggregates and the high-fat diet-induced increases in serum cholesterol levels. The levels of atherosclerosis-protecting circulating autoantibodies against copper-oxidized LDL were increased. The decrease in atherosclerotic plaque areas correlated with the reductions in weight, serum cholesterol levels, and WAT macrophage aggregates and the autoantibody increase. FG-4497 treatment stabilized HIF-1α and HIF-2α and altered the expression of glucose and lipid metabolism and inflammation-associated genes in liver and WAT. The HIF-P4H-2-hypomorphic/C699Y-LDL receptor-mutant mice likewise had a ≈50% reduction in atherosclerotic plaque areas, reduced WAT macrophage aggregate numbers, and increased autoantibodies against oxidized LDL, but did not have reduced serum cholesterol levels.
  
  
  CONCLUSIONS
  HIF-P4H-2 inhibition may be a novel strategy for protecting against the development of atherosclerosis. The mechanisms involve beneficial modulation of the serum lipid profile and innate immune system and reduced inflammation.
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Lea
authors: L
authors: Rahtu-Korpela
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Jenni
authors: J
authors: Määttä
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Elitsa Y
authors: EY
authors: Dimova
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Sohvi
authors: S
authors: Hörkkö
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Helena
authors: H
authors: Gylling
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Gail
authors: G
authors: Walkinshaw
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Jukka
authors: J
authors: Hakkola
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Kari I
authors: KI
authors: Kivirikko
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Johanna
authors: J
authors: Myllyharju
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.).
authors: Raisa
authors: R
authors: Serpi
authors: From the Biocenter Oulu, Faculty of Biochemistry and Molecular Medicine, Oulu Center for Cell-Matrix Research (L.R.-K., J. Määttä, E.Y.D., K.I.K., J. Myllyharju, R.S., P.K.) and Department of Medical Microbiology and Immunology, Medical Research Center (S.H.), University of Oulu, Oulu, Finland; Nordlab Oulu, Oulu University Hospital, Oulu, Finland (S.H.); Division of Internal Medicine, Department of Medicine, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (H.G.); FibroGen Inc., San Francisco, CA (G.W.); and Research Unit of Biomedicine, Pharmacology and Toxicology, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland (J.H.). peppi.koivunen@oulu.fi.
authors: Peppi
authors: P
authors: Koivunen
mesh_terms: D052436:Adipose Tissue, White / Q000187:drug effects / Q000201:enzymology; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D001018:Aortic Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D001323:Autoantibodies / Q000097:blood; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002478:Cells, Cultured; D002784:Cholesterol / Q000097:blood; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D007113:Immunity, Innate / Q000187:drug effects; D018836:Inflammation Mediators / Q000097:blood; D007333:Insulin Resistance; D008077:Lipoproteins, LDL / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic; D055550:Protein Stability; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D001323:Autoantibodies; D051792:Basic Helix-Loop-Helix Proteins; D002784:Cholesterol; D004791:Enzyme Inhibitors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D018836:Inflammation Mediators; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000099162:Endothelial PAS Domain-Containing Protein 1; C497443:Hif1a protein, mouse; C099252:oxidized low density lipoprotein; C490189:Egln1 protein, mouse
keywords: atherosclerosis; cholesterol; hypoxia; immunology; inflammation