Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis
| Autor: | Elitsa Y. Dimova, Gail Walkinshaw, Jukka Hakkola, Helena Gylling, Sohvi Hörkkö, Peppi Koivunen, Lea Rahtu-Korpela, Kari I. Kivirikko, Raisa Serpi, Jenni Määttä, Johanna Myllyharju |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Time Factors White adipose tissue Weight Gain chemistry.chemical_compound Adipocyte Basic Helix-Loop-Helix Transcription Factors Enzyme Inhibitors Aorta Cells Cultured Adiposity Mice Knockout Protein Stability Plaque Atherosclerotic Lipoproteins LDL Cholesterol Liver lipids (amino acids peptides and proteins) medicine.symptom Inflammation Mediators Cardiology and Cardiovascular Medicine medicine.medical_specialty Adipose Tissue White Aortic Diseases Inflammation Biology Hypoxia-Inducible Factor-Proline Dioxygenases 03 medical and health sciences Insulin resistance Internal medicine medicine Animals Autoantibodies Macrophages Lipid metabolism medicine.disease Atherosclerosis Hypoxia-Inducible Factor 1 alpha Subunit Immunity Innate Mice Inbred C57BL Disease Models Animal 030104 developmental biology Endocrinology chemistry Gene Expression Regulation Receptors LDL biology.protein Insulin Resistance Lipoprotein EGLN1 |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology. 36(4) |
| ISSN: | 1524-4636 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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