Human recombinant relaxin-2 does not attenuate hypertension or renal injury but exacerbates vascular dysfunction in a female mouse model of SLE

• Published in: American journal of physiology. Heart and circulatory physiology Vol. 317; no. 2; pp. H234 - H242
• Main Authors: Wolf, Victoria L, Phillips, Taylor L, Taylor, Erin B, Sasser, Jennifer M, Ryan, Michael J
• Format: Journal Article
• Language: English
• Published: United States American Physiological Society 01.08.2019
• Series: Integrative Cardiovascular Physiology and Pathophysiology
• Subjects: Albuminuria - etiology; Albuminuria - physiopathology; Animals; Antibodies, Antinuclear - blood; Antihypertensives; Arterial Pressure - drug effects; Arteries; Attenuation; Autoimmune diseases; Blood pressure; Cardiovascular diseases; Carotid arteries; Carotid Arteries - drug effects; Carotid Arteries - physiopathology; Carotid artery; Chronic conditions; Disease Models, Animal; Endothelium; Enzyme-linked immunosorbent assay; Excretion; Female; Health risks; Hypertension; Hypertension - etiology; Hypertension - physiopathology; Injuries; Lupus Erythematosus, Systemic - complications; Lupus Erythematosus, Systemic - drug therapy; Lupus Erythematosus, Systemic - immunology; Lupus Nephritis - etiology; Lupus Nephritis - physiopathology; Medical instruments; Mice; Mice, Inbred NZB; Recombinant Proteins - toxicity; Relaxin; Relaxin - toxicity; Renal function; Risk analysis; Risk factors; Rodents; Systemic lupus erythematosus; Uterus; Vasodilation; Vasodilation - drug effects; vascular function; relaxin; autoimmunity; sex hormones; hypertension; lupus
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00174.2019

Systemic lupus erythematosus (SLE) is an autoimmune disease that disproportionately affects women of reproductive age and increases their risk for developing hypertension, vascular, and renal disease. Relaxin has potential beneficial therapeutic effects in cardiovascular disease through direct actions on the vasculature. The potential therapeutic benefit of relaxin on SLE-associated cardiovascular and renal risk factors like hypertension has not previously been tested. We hypothesized that relaxin would attenuate hypertension, renal injury, and vascular dysfunction in an established female mouse model of SLE (NZBWF1 mice). Serelaxin (human recombinant relaxin-2, 0.5 mg·kg ·day ) or vehicle was administered via osmotic mini-pump for 4 wk in female control (NZW) or SLE mice between 28 and 31 wk of age. Serelaxin treatment increased uterine weights in both groups, suggesting that the Serelaxin was bioactive. Mean arterial pressure, measured by carotid artery catheter, was significantly increased in vehicle-treated SLE mice compared with vehicle-treated controls, but was not changed by Serelaxin treatment. Albumin excretion rate, measured by ELISA, was similar between vehicle- and Serelaxin-treated SLE mice and between vehicle- and Serelaxin-treated control mice. Wire myography was performed using isolated carotid arteries to assess endothelial-independent and -dependent vasodilation, and data confirm that SLE mice have impaired endothelium-independent and -dependent relaxation compared with control mice. Serelaxin treatment did not affect endothelium-independent vasodilation, but exacerbated the endothelium-dependent dysfunction. These data suggest that, contrary to our hypothesis, Serelaxin infusion does not attenuate hypertension, renal injury, or vascular dysfunction in SLE, but worsens underlying vascular endothelial dysfunction in this experimental model of SLE. These data do not support the use of human recombinant relaxin-2 as an antihypertensive in the SLE patient population. Relaxin is a peptide hormone commonly known for its role in pregnancy and for its use in recent clinical trials for the treatment of heart failure. Evidence suggests that relaxin has immunomodulatory effects; however, the potential therapeutic impact of relaxin in chronic immune mediated disease is unclear. This study tests whether recombinant human relaxin (Serelaxin) attenuates the progression of autoimmunity, and the associated cardiovascular consequences, in an experimental model of systemic lupus erythematosus.