Elke Marsch1, Jasper A F Demandt1, Thomas L Theelen1, Bibian M E Tullemans1, Kristiaan Wouters2, Mariëtte R Boon3,4, Theo H van Dijk5, Marion J Gijbels1,6,7, Ludwig J Dubois8, Steven J R Meex9, Massimiliano Mazzone10,11, Gene Hung12, Edward A Fisher13, Erik A L Biessen1,14, Mat J A P Daemen15, Patrick C N Rensen4, Peter Carmeliet16,17, Albert K Groen5, Judith C Sluimer18. 1. Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands. 2. Department of Internal Medicine, CARIM, Maastricht University, Maastricht, The Netherlands. 3. Department of Human Biology, Maastricht University, Maastricht, The Netherlands. 4. Department of Medicine, Division of Endocrinology and Einthoven Laboratory for Experimental Vascular Medicine, LUMC, Leiden, The Netherlands. 5. Department of Pediatrics/Laboratory Medicine, UMCG, Groningen, The Netherlands. 6. Department of Molecular Genetics, Maastricht University, Maastricht, The Netherlands. 7. Department of Medical Biochemistry, AMC, Amsterdam, The Netherlands. 8. Department of Radiation Oncology, MUMC, Maastricht, The Netherlands. 9. Department of Clinical Chemistry, MUMC, Maastricht, The Netherlands. 10. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, VIB, Leuven, Belgium. 11. Laboratory of Molecular Oncology and Angiogenesis, Vesalius Research Center, Department of Oncology, KU Leuven, Leuven, Belgium. 12. ISIS Pharmaceuticals, Inc., Carlsbad, USA. 13. Department of Medicine, NYU, New York, USA. 14. Institute for Cardiovascular Research, RWTH Aachen University, Aachen, Germany. 15. Department of Pathology, AMC, Amsterdam, The Netherlands. 16. Laboratory of Angiogenesis and Neurovascular Link, Vesalius Research Center, VIB, Leuven, Belgium. 17. Laboratory of Angiogenesis and Neurovascular Link, Department of Oncology, KU Leuven, Leuven, Belgium. 18. Department of Pathology, CARIM, MUMC, P. Debyelaan 25, Maastricht 6229 HX, The Netherlands judith.sluimer@maastrichtuniversity.nl.
Abstract
AIMS: 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. METHODS AND RESULTS: 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 Ly6Chigh 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: 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. METHODS AND RESULTS: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 Ly6Chigh 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. CONCLUSION: 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. Published on behalf of the European Society of Cardiology. All rights reserved.
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