| First Author | Rahtu-Korpela L | Year | 2016 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 36 |
| Issue | 4 | Pages | 608-17 |
| PubMed ID | 26848160 | Mgi Jnum | J:246928 |
| Mgi Id | MGI:5921440 | Doi | 10.1161/ATVBAHA.115.307136 |
| Citation | Rahtu-Korpela L, et al. (2016) Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis. Arterioscler Thromb Vasc Biol 36(4):608-17 |
| abstractText | 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 approximately 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-1alpha and HIF-2alpha 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 approximately 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. |
