Department of Physiology and Biophysics, University of Mississippi Medical Center , Jackson, Mississippi.
Department of Pharmacology and Toxicology, University of Mississippi Medical Center , Jackson, Mississippi.
Am J Physiol Heart Circ Physiol. 2019 Aug 1;317(2):H234-H242. doi: 10.1152/ajpheart.00174.2019. Epub 2019 May 24.
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.
系统性红斑狼疮（SLE）是一种自身免疫性疾病， disproportionately 影响育龄妇女，并增加她们患高血压、血管和肾脏疾病的风险。松弛素通过对血管的直接作用，具有治疗心血管疾病的潜在有益疗效。松弛素对 SLE 相关心血管和肾脏危险因素（如高血压）的潜在治疗益处尚未得到检验。我们假设松弛素会在已建立的 SLE 雌性小鼠模型（NZBWF1 小鼠）中减轻高血压、肾脏损伤和血管功能障碍。在 28 至 31 周龄的雌性对照（NZW）或 SLE 小鼠中，通过渗透微型泵给予 Serelaxin（人重组松弛素-2，0.5mg·kg·day）或载体 4 周。Serelaxin 治疗增加了两组的子宫重量，表明 Serelaxin 具有生物活性。通过颈动脉导管测量的平均动脉压在 vehicle-treated SLE 小鼠中显着高于 vehicle-treated 对照小鼠，但 Serelaxin 治疗并未改变。通过 ELISA 测量的白蛋白排泄率在 vehicle-和 Serelaxin-treated SLE 小鼠以及 vehicle-和 Serelaxin-treated 对照小鼠之间相似。使用分离的颈动脉进行wire myography 以评估内皮非依赖性和依赖性血管舒张，数据证实 SLE 小鼠与对照小鼠相比，内皮非依赖性和依赖性舒张受损。Serelaxin 治疗不影响内皮非依赖性血管舒张，但加重了内皮依赖性功能障碍。这些数据表明，与我们的假设相反，Serelaxin 输注并不能减轻 SLE 中的高血压、肾脏损伤或血管功能障碍，但会加重这种 SLE 实验模型中潜在的血管内皮功能障碍。这些数据不支持在 SLE 患者人群中使用人重组松弛素-2 作为抗高血压药物。松弛素是一种肽激素，通常因其在妊娠中的作用以及在最近心力衰竭治疗的临床试验中的用途而为人所知。有证据表明，松弛素具有免疫调节作用；然而，松弛素在慢性免疫介导性疾病中的潜在治疗作用尚不清楚。本研究测试了重组人松弛素（Serelaxin）是否能减轻系统性红斑狼疮实验模型中自身免疫的进展及其相关心血管后果。
