Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, 277# 138 Yixueyuan Road, Shanghai 200032, China.
Department of Anatomy, Histology and Embryology, Shanghai Medical School of Fudan University, 277# 138 Yixueyuan Road, Shanghai 200032, China.
Exp Cell Res. 2018 Jan 1;362(1):17-27. doi: 10.1016/j.yexcr.2017.10.004. Epub 2017 Oct 5.
Serelaxin, a recombinant form of human relaxin-2, is currently regarded as a novel drug for treatment of acute heart failure. However, whether therapeutic effects of serelaxin are achieved by inhibiting cardiac fibrosis remains unclear. In this study, we investigate effects of serelaxin on inhibiting cardiac fibrosis. Cardiac fibroblasts (CFs) were isolated from the hearts of adult rats. Effects of serelaxin on differentiation of CFs towards myofibroblasts (MFs) and their fibrotic behaviors after induction with TGF-β1 were examined. Synthesis and degradation of collagens, secretion of IL-10, and expression of ALK-5 and p-Smad2/3 of TGF-β1-induced cells were assessed after treatment with serelaxin. Serelaxin inhibited differentiation of TGF-β1-induced CFs towards MFs, and reduced proliferation and migration of the induced cells. Moreover, serelaxin down-regulated expression of collagen I/III and TIMP-2, and up-regulated expression of MMP-2 and MMP-9 in the cells. After treatment with serelaxin, activity of MMP-2 and MMP-9 and secretion of IL-10 increased, expression of ALK-5 and the level of Smad2/3 phosphorylation was reduced significantly. These results suggest that serelaxin can inhibit differentiation of TGF-β1-induced CFs towards MFs, reduce production of collagens by suppressing ALK-5/Smad2/3 signaling pathway, and enhance extracellular matrix degradation by increasing MMP-2/TIMP-2 ratio and IL-10 secretion. Serelaxin may be a potential therapeutic drug for inhibiting cardiac fibrosis.
人松弛素-2 的重组形式——赛乐瑞辛，目前被认为是一种治疗急性心力衰竭的新型药物。然而，赛乐瑞辛是否通过抑制心肌纤维化来发挥治疗作用尚不清楚。本研究旨在探讨赛乐瑞辛对抑制心肌纤维化的作用。从成年大鼠心脏中分离出心肌成纤维细胞（CFs）。观察赛乐瑞辛对 TGF-β1 诱导的 CFs 向肌成纤维细胞（MFs）分化以及分化后纤维化行为的影响。用赛乐瑞辛处理 TGF-β1 诱导的细胞后，评估其胶原合成与降解、IL-10 分泌以及 ALK-5 和磷酸化 Smad2/3 的表达。赛乐瑞辛抑制了 TGF-β1 诱导的 CFs 向 MFs 的分化，并减少了诱导细胞的增殖和迁移。此外，赛乐瑞辛下调了细胞中胶原 I/III 和 TIMP-2 的表达，上调了 MMP-2 和 MMP-9 的表达。用赛乐瑞辛处理后，MMP-2 和 MMP-9 的活性以及 IL-10 的分泌增加，ALK-5 的表达和 Smad2/3 磷酸化水平显著降低。这些结果表明，赛乐瑞辛可通过抑制 ALK-5/Smad2/3 信号通路抑制 TGF-β1 诱导的 CFs 向 MFs 的分化，并通过增加 MMP-2/TIMP-2 比值和 IL-10 分泌来增强细胞外基质的降解。赛乐瑞辛可能是一种抑制心肌纤维化的潜在治疗药物。
