H3 Relaxin Demonstrates Antifibrotic Properties via the RXFP1 Receptor
H3 Relaxin Demonstrates Antifibrotic Properties via the RXFP1 Receptor
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DOI：
10.1021/bi1013968
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发表时间：
2011-03-01
期刊：
影响因子：
2.9
通讯作者：
Samuel, Chrishan S.
中科院分区：
文献类型：
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作者：
Hossain, Mohammed Akhter;Man, Bryna Chow Suet;Samuel, Chrishan S.
人类基因 3 (H3) 松弛素是松弛素肽家族中最新发现的成员，可以潜在地结合所有定义的松弛素家族肽受体 (RXFP1-4)。虽然人们越来越多地通过其主要受体 RXFP3 研究其作为神经调节剂的作用，但对其通过其他 RXFP 的作用却知之甚少。因此，我们利用体外原代大鼠心室成纤维细胞（天然表达 RXFP1，但不表达 RXFP3）和体内纤维化心肌病小鼠模型，专门确定了 H3 松弛素通过 RXFP1 受体的抗纤维化作用和作用机制。向心室成纤维细胞施用转化生长因子 β 1 (TGF-β 1) 显着增加 Smad2 磷酸化、肌成纤维细胞分化和胶原沉积（与未处理对照相比，所有 p < 0.05），而对基质金属蛋白酶 (MMP) 9、MMP-13、金属蛋白酶组织抑制剂 (TIMP) 1 没有明显影响， 或 TIMP-2 表达超过 72 小时。 H3松弛素（100和250 ng/mL）在72小时内几乎完全消除了TGF-β1刺激的胶原蛋白沉积，其100 ng/mL的效果与相同剂量的H2松弛素的效果相当。此外，H3 松弛素 (100 ng/mL) 显着抑制 TGF-β 1 刺激的心肌成纤维细胞分化以及 TIMP-1 和 TIMP-2 表达，其程度与 H2 松弛素 (100 ng/mL) 相当，同时抑制 Smad2 磷酸化的程度约为 H2 松弛素的一半（与 TGF-β 1 相比，所有 p < 0.05）。较低剂量的 H3 (50 ng/mL) 和 H2 (50 ng/mL) 松弛素在体外可进一步抑制 TGF-β1 刺激的胶原蛋白沉积，同时还发现 H3 松弛素在体内纤维化心肌病模型中可逆转左心室胶原蛋白过度表达。这些综合发现表明，H3 具有抗纤维化作用；通过 RXFP1 发挥作用，并可能增强 H2 松弛素的胶原蛋白抑制作用。
Human gene 3 (H3) relaxin is the most recently discovered member of the relaxin peptide family and can potentially bind all of the defined relaxin family peptide receptors (RXFP1-4). While its effects as a neuromodulator are being increasingly studied through its primary receptor, RXFP3, its actions via other RXFPs are poorly understood. Hence, we specifically determined the antifibrotic effects and mechanisms of action of H3 relaxin via the RXFP1 receptor using primary rat ventricular fibroblasts in vitro, which naturally express RXFP1, but not RXFP3, and a mouse model of fibrotic cardiomyopathy in vivo. Transforming growth factor beta 1 (TGF-beta 1) administration to ventricular fibroblasts significantly increased Smad2 phosphorylation, myofibroblast differentiation, and collagen deposition (all p < 0.05 vs untreated controls), while having no marked effect on matrix metalloproteinase (MMP) 9, MMP-13, tissue inhibitor of metalloproteinase (TIMP) 1, or TIMP-2 expression over 72 h. H3 relaxin (at 100 and 250 ng/mL) almost completely abrogated the TGF-beta 1-stimulated collagen deposition over 72 h, and its effects at 100 ng/mL were equivalent to that of the same dose of H2 relaxin. Furthermore, H3 relaxin (100 ng/mL) significantly inhibited TGF-beta 1-stimulated cardiac myofibroblast differentiation and TIMP-1 and TIMP-2 expression to an equivalent extent as H2 relaxin (100 ng/mL), while also inhibiting Smad2 phosphorylation to approximately half the extent of H2 relaxin (all p < 0.05 vs TGF-beta 1). Lower doses of H3 (50 ng/mL) and H2 (50 ng/mL) relaxin additively inhibited TGF-beta 1-stimulated collagen deposition in vitro, while H3 relaxin was also found to reverse left ventricular collagen overexpression in the model of fibrotic cardiomyopathy in vivo. These combined findings demonstrate that H3 relax in exerts antifibrotic; actions via RXFP1 and may enhance the collagen-inhibitory effects of H2 relaxin.