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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 (?2GPI) and hypertension. A1-A1 is a soluble analogue of ApoE receptor 2 with a high affinity for ?2GPI/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-?2GPI antibodies, microinfarcts and hypertension. ApoER2 is a receptor that contributes to anti-?2GPI-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 ?2GPI. 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 ?2GPI/anti-?2GPI complexes, has a positive impact on hemodynamics in lupus-prone mice with spontaneous anti-?2GPI antibodies and hypertension.

SUBMITTER: Kolyada A

PROVIDER: S-EPMC4998045 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.

Kolyada A A Ke Q Q Karageorgos I I Mahlawat P P Barrios D A DA Kang P M PM Beglova N N

Journal of thrombosis and haemostasis : JTH 20160503 6

<h4>Unlabelled</h4>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.<h4>Summary</h4>Background Antiphospholipid syndrome (APS) is diagnosed based on the presence of antiphospholipid antibodies and clinical ...[more]

PMID: 26990752

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Project description:ObjectiveAntiphospholipid antibodies (aPL) constitute a diagnostic criterion of systemic lupus erythematosus (SLE), and aPL have been functionally linked to liver disease in patients with SLE. Since the mechanistic target of rapamycin (mTOR) is a regulator of oxidative stress, a pathophysiologic process that contributes to the development of aPL, this study was undertaken in a mouse model of SLE to examine the involvement of liver mitochondria in lupus pathogenesis.MethodsMitochondria were isolated from lupus-prone MRL/lpr, C57BL/6.lpr, and MRL mice, age-matched autoimmunity-resistant C57BL/6 mice as negative controls, and transaldolase-deficient mice, a strain that exhibits oxidative stress in the liver. Electron transport chain (ETC) activity was assessed using measurements of oxygen consumption. ETC proteins, which are regulators of mitochondrial homeostasis, and the mTOR complexes mTORC1 and mTORC2 were examined by Western blotting. Anticardiolipin (aCL) and anti-β2 -glycoprotein I (anti-β2 GPI) autoantibodies were measured by enzyme-linked immunosorbent assay in mice treated with rapamycin or mice treated with a solvent control.ResultsMitochondrial oxygen consumption was increased in the livers of 4-week-old, disease-free MRL/lpr mice relative to age-matched controls. Levels of the mitophagy initiator dynamin-related protein 1 (Drp1) were depleted while the activity of mTORC1 was increased in MRL/lpr mice. In turn, mTORC2 activity was decreased in MRL and MRL/lpr mice. In addition, levels of aCL and anti-β2 GPI were elevated preceding the development of nephritis in 4-week-old MRL, C57BL/6.lpr, and MRL/lpr mice. Transaldolase-deficient mice showed increased oxygen consumption, depletion of Drp1, activation of mTORC1, and elevated expression of NADH:ubiquinone oxidoreductase core subunit S3 (NDUFS3), a pro-oxidant subunit of ETC complex I, as well as increased production of aCL and anti-β2 GPI autoantibodies. Treatment with rapamycin selectively blocked mTORC1 activation, NDUFS3 expression, and aPL production both in transaldolase-deficient mice and in lupus-prone mice.ConclusionIn lupus-prone mice, mTORC1-dependent mitochondrial dysfunction contributes to the generation of aPL, suggesting that such mechanisms may represent a treatment target in patients with SLE.

Dataset Information

Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.

Publications

Soluble analog of ApoER2 targeting beta2-glycoprotein I in immune complexes counteracts hypertension in lupus-prone mice with spontaneous antiphospholipid syndrome.

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