TY - JOUR
T1 - Deficiency of the oxygen sensor prolyl hydroxylase 1 attenuates hypercholesterolaemia, atherosclerosis, and hyperglycaemia
AU - Marsch, Elke
AU - Demandt, Jasper A. F.
AU - Theelen, Thomas L.
AU - Tullemans, Bibian M. E.
AU - Wouters, Kristiaan
AU - Boon, Mariette R.
AU - van Dijk, Theo H.
AU - Gijbels, Marion J.
AU - Dubois, Ludwig J.
AU - Meex, Steven J. R.
AU - Mazzone, Massimiliano
AU - Hung, Gene
AU - Fisher, Edward A.
AU - Biessen, Erik A. L.
AU - Daemen, Mat J. A. P.
AU - Rensen, Patrick C. N.
AU - Carmeliet, Peter
AU - Groen, Albert K.
AU - Sluimer, Judith C.
PY - 2016/10/14
Y1 - 2016/10/14
N2 - 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.
AB - 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.
KW - Oxygen sensor
KW - Cholesterol and lipids
KW - Hyperglycaemia
KW - Atherosclerosis
KW - Inflammation
U2 - 10.1093/eurheartj/ehw156
DO - 10.1093/eurheartj/ehw156
M3 - Article
C2 - 27125949
SN - 0195-668X
VL - 37
SP - 2993
EP - 2997
JO - European Heart Journal
JF - European Heart Journal
IS - 39
ER -