Protection from cigarette smoke‐induced vascular injury by recombinant human relaxin‐2 (serelaxin)

Abstract

Smoking is regarded as a major risk factor for the development of cardiovascular diseases (CVD). This study investigates whether serelaxin (RLX, recombinant human relaxin‐2) endowed with promising therapeutic properties in CVD, can be credited of a protective effect against cigarette smoke (CS)‐induced vascular damage and dysfunction. Guinea pigs exposed daily to CS for 8 weeks were treated with vehicle or RLX, delivered by osmotic pumps at daily doses of 1 or 10 μg. Controls were non‐smoking animals. Other studies were performed on primary guinea pig aortic endothelial (GPAE) cells, challenged with CS extracts (CSE) in the absence and presence of 100 ng/ml (17 nmol/l) RLX. In aortic specimens from CS‐exposed guinea pigs, both the contractile and the relaxant responses to phenylephrine and acetylcholine, respectively, were significantly reduced in amplitude and delayed, in keeping with the observed adverse remodelling of the aortic wall, endothelial injury and endothelial nitric oxide synthase (eNOS) down‐regulation. RLX at both doses maintained the aortic contractile and relaxant responses to a control‐like pattern and counteracted aortic wall remodelling and endothelial derangement. The experiments with GPAE cells showed that CSE significantly decreased cell viability and eNOS expression and promoted apoptosis by sparkling oxygen free radical‐related cytotoxicity, while RLX counterbalanced the adverse effects of CSE. These findings demonstrate that RLX is capable of counteracting CS‐mediated vascular damage and dysfunction by reducing oxidative stress, thus adding a tile to the growing mosaic of the beneficial effects of RLX in CVD.

Intraarticular injection of relaxin-2 alleviates shoulder arthrofibrosis

“…Encouraging results from both cell and animal studies support further development and clinical evaluation of relaxin-2 as a first-in-kind therapy for arthrofibroses. the heart, lungs, kidney, and liver (30)(31)(32)(33)(34)(35). Our proposal stems from anecdotal clinical observation among a cohort of arthrofibrosis-afflicted female patients who experienced lasting motion restoration and reduced joint pain during and after pregnancy (E.K.R.).…”

Serelaxin enhances the therapeutic effects of human amnion epithelial cell‐derived exosomes in experimental models of lung disease

“…Shown is the relative mean ± SEM dynamic lung compliance from control (saline), BLM-injured mice and from the various treatment groups investigated against BLM-induced pulmonary fibrosis, in response to the highest dose of methacholine evaluated (50 mg·ml −1 ). *P < 0.05, significantly different from the control group (SAL) ; # P < 0.05, significantly different from the BLM-treated group mast cells (Bani, Ballati, Masini, Bigazzi, & Sacchi, 1997), leukocytes (Bani et al, 1997;Pini, Boccalini, Lucarini, et al, 2016), and neutrophils (Masini et al, 2004) and suppressing the pro-inflammatory and profibrotic actions of TGF-β1 (Royce, Lim, et al, 2014;Unemori et al, 1996), TNF-α, IL-1β, and/or IL-18 (Brecht, Bartsch, Baumann, Stangl, & Dschietzig, 2011;Pini, Boccalini, Baccari, et al, 2016). Furthermore, serelaxin inhibits fibrosis by preventing fibroblast proliferation and differentiation into myofibroblasts as a means of limiting myofibroblastmediated ECM deposition Royce et al, 2015Royce et al, , 2016.…”

“…Combining exosomes with serelaxin could also have promoted synergistic actions through the activation of overlapping and distinct pathways. Serelaxin can inhibit the contribution of lung inflammation on fibrosis by reducing the infiltration and activation of mast cells (Bani, Ballati, Masini, Bigazzi, & Sacchi, ), leukocytes (Bani et al, ; Pini, Boccalini, Lucarini, et al, ), and neutrophils (Masini et al, ) and suppressing the pro‐inflammatory and pro‐fibrotic actions of TGF‐β1 (Royce, Lim, et al, ; Unemori et al, ), TNF‐α, IL‐1β, and/or IL‐18 (Brecht, Bartsch, Baumann, Stangl, & Dschietzig, ; Pini, Boccalini, Baccari, et al, ). Furthermore, serelaxin inhibits fibrosis by preventing fibroblast proliferation and differentiation into myofibroblasts as a means of limiting myofibroblast‐mediated ECM deposition (Huuskes et al, ; Royce et al, , ).…”

Relaxin as a Therapeutic Target for the Cardiovascular Complications of Diabetes

“…These studies in hypertensive models clearly show the vasculoprotective effects of relaxin against hypertension-induced dysfunction and its potential role in reversing hypertension-associated fibrosis. More recently, relaxin treatment is reported to reverse cigarette smoke-induced endothelial dysfunction, an effect attributed to enhanced endothelial NO synthase (eNOS) expression ( Pini et al, 2016 ). Relaxin infusion over 4 weeks also reverses the atherosclerosis-associated endothelial dysfunction in ApoE -/- mice, an effect attributed to reduction in angiotensin AT1 receptors and oxidative stress ( Tiyerili et al, 2016 ).…”