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

Elke Marsch, Jasper A. F. Demandt, Thomas L. Theelen, Bibian M. E. Tullemans, Kristiaan Wouters, Mariette R. Boon, Theo H. van Dijk, Marion J. Gijbels, Ludwig J. Dubois, Steven J. R. Meex, Massimiliano Mazzone, Gene Hung, Edward A. Fisher, Erik A. L. Biessen, Mat J. A. P. Daemen, Patrick C. N. Rensen, Peter Carmeliet, Albert K. Groen, Judith C. Sluimer*

*Corresponding author for this work

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Abstract

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(high) 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.
Original languageEnglish
Pages (from-to)2993-2997
JournalEuropean Heart Journal
Volume37
Issue number39
DOIs
Publication statusPublished - 14 Oct 2016

Keywords

  • Oxygen sensor
  • Cholesterol and lipids
  • Hyperglycaemia
  • Atherosclerosis
  • Inflammation

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