Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia

• Published in: European heart journal 2016-10, Vol.37 (39), p.2993-2997
• Main Authors: Marsch, Elke, Demandt, Jasper A F, Theelen, Thomas L, Tullemans, Bibian M E, Wouters, Kristiaan, Boon, Mariëtte R, van Dijk, Theo H, Gijbels, Marion J, Dubois, Ludwig J, Meex, Steven J R, Mazzone, Massimiliano, Hung, Gene, Fisher, Edward A, Biessen, Erik A L, Daemen, Mat J A P, Rensen, Patrick C N, Carmeliet, Peter, Groen, Albert K, Sluimer, Judith C
• Format: Article
• Language: English
• Subjects: Animals; Atherosclerosis; Disease Models, Animal; Editor's Choice; EHJ Brief Communication; Hypercholesterolemia; Hyperglycemia; Mice; Mice, Inbred C57BL; Mice, Knockout; Oxygen; Prolyl Hydroxylases; Receptors, LDL
• ISSN: 0195-668X; 1522-9645
• DOI: 10.1093/eurheartj/ehw156

Normalization of hypercholesterolaemia, inflammation, hyperglycaemia, and obesity are main desired targets to prevent cardiovascular clinical events. Here we present a novel regulator of cholesterol metabolism, which simultaneously impacts on glucose intolerance and inflammation. Mice deficient for oxygen sensor HIF-prolyl hydroxylase 1 (PHD1) were backcrossed onto an atherogenic low-density lipoprotein receptor (LDLR) knockout background and atherosclerosis was studied upon 8 weeks of western-type diet. PHD1 LDLR mice presented a sharp reduction in VLDL and LDL plasma cholesterol levels. In line, atherosclerotic plaque development, as measured by plaque area, necrotic core expansion and plaque stage was hampered in PHD1 LDLR mice. Mechanistically, cholesterol-lowering in PHD1 deficient mice was a result of enhanced cholesterol excretion from blood to intestines and ultimately faeces. Additionally, flow cytometry of whole blood of these mice revealed significantly reduced counts of leucocytes and particularly of Ly6C pro-inflammatory monocytes. In addition, when studying PHD1 in diet-induced obesity (14 weeks high-fat diet) mice were less glucose intolerant when compared with WT littermate controls. Overall, PHD1 knockout mice display a metabolic phenotype that generally is deemed protective for cardiovascular disease. Future studies should focus on the efficacy, safety, and gender-specific effects of PHD1 inhibition in humans, and unravel the molecular actors responsible for PHD1-driven, likely intestinal, and regulation of cholesterol metabolism.