Lea Rahtu-Korpela1, Jenni Määttä1, Elitsa Y Dimova1, Sohvi Hörkkö1, Helena Gylling1, Gail Walkinshaw1, Jukka Hakkola1, Kari I Kivirikko1, Johanna Myllyharju1, Raisa Serpi1, Peppi Koivunen2. 1. 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.). 2. 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.
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. APPROACH AND 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.
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. APPROACH AND 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: Mikko N M Myllymäki; Jenni Määttä; Elitsa Y Dimova; Valerio Izzi; Timo Väisänen; Johanna Myllyharju; Peppi Koivunen; Raisa Serpi Journal: Mol Cell Biol Date: 2017-01-04 Impact factor: 4.272
Authors: Hong S Lu; Ann Marie Schmidt; Robert A Hegele; Nigel Mackman; Daniel J Rader; Christian Weber; Alan Daugherty Journal: Arterioscler Thromb Vasc Biol Date: 2018-10 Impact factor: 8.311
Authors: Jasper A F Demandt; Kim van Kuijk; Thomas L Theelen; Elke Marsch; Sean P Heffron; Edward A Fisher; Peter Carmeliet; Erik A L Biessen; Judith C Sluimer Journal: Front Cell Dev Biol Date: 2021-05-14
Authors: Shuang Feng; Neil Bowden; Maria Fragiadaki; Celine Souilhol; Sarah Hsiao; Marwa Mahmoud; Scott Allen; Daniela Pirri; Blanca Tardajos Ayllon; Shamima Akhtar; A A Roger Thompson; Hanjoong Jo; Christian Weber; Victoria Ridger; Andreas Schober; Paul C Evans Journal: Arterioscler Thromb Vasc Biol Date: 2017-09-07 Impact factor: 10.514