Recombinant Human Relaxin‐2 Treatment in an Experimental Female Mouse Model of Autoimmune Disease with Hypertension

Abstract

Relaxin is a peptide hormone commonly known for its role during pregnancy; however, it has been postulated to have beneficial therapeutic effects in cardiovascular disease through direct actions on the vasculature. Systemic lupus erythematosus (SLE) is an autoimmune disease that, for reasons that are not completely understood, disproportionately affects women of reproductive age and increases their risk for developing hypertension, cardiovascular and renal disease. The potential therapeutic benefit of relaxin on SLE associated cardiovascular and renal risk factors like hypertension has not previously been tested. The objective of this study was to test the efficacy of relaxin to attenuate hypertension, renal injury, and vascular dysfunction in an established female mouse model of SLE (NZBWF1 mice). To test this, Serelaxin (human recombinant relaxin‐2, 0.5 mg/kg/day) or vehicle (saline) was administered via osmotic mini‐pump (Alzet 1002) for 4 weeks in NZW (Control) or SLE mice between 28 and 31 weeks of age. Mean arterial pressure was measured by carotid artery catheters in conscious mice at the conclusion of the study. Urinary albumin excretion, a marker of renal injury, was determined at the conclusion of the study by albumin ELISA in overnight samples collected in metabolic cages. Wire myography was performed using isolated carotid arteries to assess endothelial‐independent and –dependent vasodilation in response to increasing concentrations of sodium nitroprusside and acetylcholine, respectively (10−8–10−4 M). Serelaxin‐treated control and SLE mice had significantly increased uterine weights (p<0.05) compared to vehicle‐treated mice, suggesting that the Serelaxin was bioactive. Mean arterial pressure was significantly increased in vehicle‐treated SLE mice compared to vehicle treated controls (134 ± 5 mmHg vs. 111 ± 3, n=9–12, p<0.05). Blood pressure was not changed in Serelaxin‐treated SLE (139 ± 5 mmHg, n=12) or control mice (115 ± 3 mmHg, n=10). Albumin excretion rate was similar between vehicle‐(23.6 ± 17.5 mg/day, n =11) and Serelaxin‐treated (35.7 ± 16.1 mg/day, n= 11) SLE mice, and between vehicle (1.1 ± 0.9 mg/day, n=15) and Serelaxin‐treated (0.1 ± 0.1 mg/day, n=13) control mice. Wire myography data confirm previously published studies showing that SLE mice have impaired endothelial‐independent (Figure 1) and ‐dependent (Figure 2) relaxation compared to control mice. Serelaxin treatment did not affect endothelial‐independent vasodilation, but appears to have exacerbated the endothelial‐dependent dysfunction. These data suggest that, contrary to our hypothesis, Serelaxin infusion does not attenuate hypertension, renal injury, or vascular dysfunction in SLE under these experimental conditions. In fact, Serelaxin, through its direct actions on the vasculature, may worsen the underlying vascular endothelial dysfunction in this experimental model of SLE.Support or Funding InformationVA Merit Award (BX002604‐01A2), AHA 18PRE34020108, NIH (P01HL051971, P20GM104357, U54GM115428, R01HL134711, T32HL105324‐05)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.