Hypoxia-Inducible Factor Prolyl 4-Hydroxylase-2 Inhibition Protects Against Development of Atherosclerosis. Issue 4 (April 2016)

• Record Type: Journal Article
• Authors: Rahtu-Korpela, Lea; Määttä, Jenni; Dimova, Elitsa Y.; Hörkkö, Sohvi; Gylling, Helena; Walkinshaw, Gail; Hakkola, Jukka; Kivirikko, Kari I.; Myllyharju, Johanna; Serpi, Raisa; Koivunen, Peppi
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 36:Issue 4(2016)
• Publication Date: 2016-04
• Subjects: atherosclerosis -- cholesterol -- hypoxia -- immunology -- inflammation; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.115.307136
• Languages: English
• ISSNs: 1079-5642

Abstract

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. Abstract : Supplemental Digital Content is available in the text.