title: Prolactin receptor antagonism uncouples lipids from atherosclerosis susceptibility.
abstract: The pituitary-derived hormone prolactin has been suggested to stimulate the development of atherosclerosis and cardiovascular disease through its effects on metabolism and inflammation. In this study, we aimed to challenge the hypothesis that inhibition of prolactin function may beneficially affect atherosclerosis burden. Hereto, atherosclerosis-susceptible LDL receptor (Ldlr) knockout mice were transplanted with bone marrow from transgenic mice expressing the pure prolactin receptor antagonist Del1-9-G129R-hPRL or their non-transgenic littermates as control. Recipient mice expressing Del1-9-G129R-hPRL exhibited a decrease in plasma cholesterol levels (-29%; P<0.05) upon feeding a Western-type diet (WTD), which could be attributed to a marked decrease (-47%; P<0.01) in the amount of cholesterol esters associated with pro-atherogenic lipoproteins VLDL/LDL. By contrast, Del1-9-G129R-hPRL-expressing mice did not display any change in the susceptibility for atherosclerosis after 12 weeks of WTD feeding. Both the absolute atherosclerotic lesion size (223 ± 33 × 10(3) μm(2) for Del1-9-G129R-hPRL vs 259 ± 32 × 10(3) μm(2) for controls) and the lesional macrophage and collagen contents were not different between the two groups of bone marrow recipients. Importantly, Del1-9-G129R-hPRL exposure increased levels of circulating neutrophils (+91%; P<0.05), lymphocytes (+55%; P<0.05), and monocytes (+43%; P<0.05), resulting in a 49% higher (P<0.01) total blood leukocyte count. In conclusion, we have shown that prolactin receptor signaling inhibition uncouples the plasma atherogenic index from atherosclerosis susceptibility in Ldlr knockout mice. Despite an associated decrease in VLDL/LDL cholesterol levels, application of the prolactin receptor antagonist Del1-9-G129R-hPRL does not alter the susceptibility for initial development of atherosclerotic lesions probably due to the parallel increase in circulating leukocyte concentrations.
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Ronald J
authors: RJ
authors: van der Sluis
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Tim
authors: T
authors: van den Aardweg
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Anne Q
authors: AQ
authors: Reuwer
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Marcel T
authors: MT
authors: Twickler
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Florence
authors: F
authors: Boutillon
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Miranda
authors: M
authors: Van Eck
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France.
authors: Vincent
authors: V
authors: Goffin
authors: Division of BiopharmaceuticsGorlaeus Laboratories, Leiden Academic Centre for Drug Research, Einsteinweg 55, 2333CC Leiden, The NetherlandsLaboratory for Microbiology and Infection ControlAmphia Hospital, Breda, The NetherlandsDepartment EndocrinologyDiabetology and Metabolic Diseases, Antwerp University Hospital, Antwerp, BelgiumInsermUnit 1151,Prolactin/Growth Hormone Pathophysiology Laboratory, Faculty of Medicine, Institut Necker Enfants Malades (INEM), University Paris Descartes, Sorbonne Paris Cité, Paris, France hoekstra@lacdr.leidenuniv.nl.
authors: Menno
authors: M
authors: Hoekstra
mesh_terms: D000818:Animals; D001011:Aorta / Q000473:pathology; D050197:Atherosclerosis / Q000209:etiology* / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016026:Bone Marrow Transplantation; D004198:Disease Susceptibility; D015870:Gene Expression; D007962:Leukocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011388:Prolactin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011981:Receptors, Prolactin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D011973:Receptors, LDL; D011981:Receptors, Prolactin; D011994:Recombinant Proteins; C402398:prolactin, Arg(129)-; D011388:Prolactin
keywords: Del1-9-G129R-hPRL; atherosclerosis; lipoprotein; mouse model; prolactin receptor