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.

Summary: 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.

Keywords: Apo H; antiphospholipid syndrome; beta2-glycoprotein I; hypertension; low-density lipoprotein receptor-related protein 8.

Fig. 1

Serum levels of anti-β2GPI antibodies and anti-dsDNA antibodies in (NZWxBXSB)F1 mice. The dot plots show the median value for each group (black bars) and P values between two groups. U, untreated; V, treated with a vehicle; A, treated with A1-A1. Age-matched groups: 10UVA (n = 6), 10-week-old mice untreated (U) and treated from 8 to 10 weeks of age (V and A); 12UVA (n = 8–10), 12-week-old mice untreated (U) and treated from 8 to 12 weeks of age (V and A); 14UVA (n = 8–10, male) and 14UA (n = 7, female), 14-week-old mice untreated (U) and treated from 10 to 14 weeks of age (V and A); 8U (n = 6), 8-week-old untreated; 16U (n = 8), 16-week-old untreated. *P value < 0.05; **P value < 0.005; ns, not significant.

Fig. 2

Systemic blood pressure in (NZWxBXSB)F1 mice. Systolic pressure, black bars; diastolic pressure, grey bars. Data are presented as mean ± SD. U, untreated; V, treated with a vehicle; A, treated with A1-A1. P values are specified in Table 1