Department of Experimental & Clinical Medicine, Section of Anatomy & Histology & Research Unit of Histology & Embryology, University of Florence, Florence, Italy.
Section of Physiology, University of Florence, Florence, Italy.
J Cell Mol Med. 2016 May;20(5):891-902. doi: 10.1111/jcmm.12802. Epub 2016 Feb 24.
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.
吸烟被认为是心血管疾病（CVD）发展的主要危险因素。本研究探讨了具有治疗 CVD 前景的松弛素（RLX，重组人松弛素-2）是否可以防止香烟烟雾（CS）引起的血管损伤和功能障碍。将豚鼠每天暴露于 CS 中 8 周，并用渗透泵以 1 或 10μg/天的剂量给予载体或 RLX 治疗。对照组为不吸烟的动物。其他研究在原代豚鼠主动脉内皮（GPAE）细胞上进行，这些细胞在缺乏和存在 100ng/ml（17nmol/l）RLX 的情况下，用 CS 提取物（CSE）进行挑战。在 CS 暴露的豚鼠的主动脉标本中，对苯肾上腺素和乙酰胆碱的收缩和舒张反应的幅度均显著降低，且延迟，与观察到的主动脉壁的不利重塑、内皮损伤和内皮型一氧化氮合酶（eNOS）下调一致。RLX 在两种剂量下均维持了主动脉的收缩和舒张反应，使其模式类似于对照，并对抗了主动脉壁重塑和内皮紊乱。在 GPAE 细胞的实验中，CSE 显著降低了细胞活力和 eNOS 表达，并通过促进与氧自由基相关的细胞毒性而促进细胞凋亡，而 RLX 则抵消了 CSE 的不良影响。这些发现表明，RLX 通过降低氧化应激来抵抗 CS 介导的血管损伤和功能障碍，从而为 RLX 在 CVD 中的有益作用不断增加的拼图增添了一个板块。
