title: Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.
abstract: Essentials (NZWxBXSB)F1 male mice develop antibodies beta2-glycoprotein I (β2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for β2GPI/antibody complexes. A1-A1 improved blood pressure and arterial elastance in (NZWxBXSB)F1 male mice. A1-A1 had no adverse effects on the hemodynamics of healthy mice.
  
  
  
  Background Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical thrombosis or fetal loss during pregnancy. Lupus-prone (NZWxBXSB)F1 male mice are the mouse model of spontaneous APS. They develop anti-β2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-β2GPI-dependent thrombosis in APS by down-regulating endothelial nitric oxide synthase activation. Objectives A1-A1 is a small protein constructed from two identical ligand-binding modules from ApoER2, containing the binding site for β2GPI. We studied how treatment with A1-A1 affects the development of hypertension in (NZWxBXSB)F1 male mice. Methods We treated (NZWxBXSB)F1 male mice with A1-A1 for up to 4 weeks and examined changes in hemodynamics by left ventricular pressure-volume loop measurements. Results We observed improvements in blood pressure in the A1-A1 treated mice. A1-A1 prevented the deterioration of arterial elastance by decreasing systemic resistance and improving vessel compliance. We did not detect any adverse effects of the treatment in either male mice or in apparently healthy female (NZWxBXSB)F1 mice. Conclusions We demonstrated that A1-A1, which is a soluble analog of ApoER2 that binds pathological β2GPI/anti-β2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-β2GPI antibodies and hypertension.
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Kolyada
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Ke
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: I
authors.initials: I
authors.lastname: Karageorgos
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: P
authors.initials: P
authors.lastname: Mahlawat
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Barrios
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: P M
authors.initials: PM
authors.lastname: Kang
authors.affiliation: Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Beglova
mesh_terms: D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000276:immunology; D000936:Antigen-Antibody Complex; D016736:Antiphospholipid Syndrome / Q000097:blood* / Q000276:immunology; D001794:Blood Pressure; D004195:Disease Models, Animal; D004548:Elasticity; D005260:Female; D006439:Hemodynamics; D006801:Humans; D006973:Hypertension / Q000378:metabolism; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000097:blood* / Q000378:metabolism*; D008024:Ligands; D050356:Lipid Metabolism; D008181:Lupus Nephritis / Q000097:blood / Q000276:immunology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D012995:Solubility; D013927:Thrombosis / Q000473:pathology; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D017152:Antibodies, Antiphospholipid; D000936:Antigen-Antibody Complex; D007074:Immunoglobulin G; D026502:LDL-Receptor Related Proteins; D008024:Ligands; D053482:beta 2-Glycoprotein I; C098773:low density lipoprotein receptor-related protein 8; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: Apo H; antiphospholipid syndrome; beta2-glycoprotein I; hypertension; low-density lipoprotein receptor-related protein 8