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首页> 外文期刊>Biochemistry >H3 Relaxin Demonstrates Antifibrotic Properties via the RXFP1 Receptor
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H3 Relaxin Demonstrates Antifibrotic Properties via the RXFP1 Receptor

机译：H3 Relaxin通过RXFP1受体表现出抗纤维化特性

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Human gene 3 (H3) relaxin is the most recently discovered member of the relaxin peptide familynand can potentially bind all of the defined relaxin family peptide receptors (RXFP1-4).While its effects as anneuromodulator are being increasingly studied through its primary receptor, RXFP3, its actions via othernRXFPs are poorly understood. Hence, we specifically determined the antifibrotic effects and mechanisms ofnaction ofH3 relaxin via the RXFP1 receptor using primary rat ventricular fibroblasts in vitro, which naturallynexpress RXFP1, but not RXFP3, and a mouse model of fibrotic cardiomyopathy in vivo. Transformingngrowth factor β1 (TGF-β1) administration to ventricular fibroblasts significantly increased Smad2 phos-nphorylation,myofibroblast differentiation, and collagen deposition (all p<0.05 vs untreated controls), whilenhaving no marked effect on matrix metalloproteinase (MMP) 9, MMP-13, tissue inhibitor of metallopro-nteinase (TIMP) 1, or TIMP-2 expression over 72 h. H3 relaxin (at 100 and 250 ng/mL) almost completelynabrogated the TGF-β1-stimulated collagen deposition over 72 h, and its effects at 100 ng/mL were equivalentnto that of the same dose of H2 relaxin. Furthermore, H3 relaxin (100 ng/mL) significantly inhibited TGF-β1-nstimulated cardiac myofibroblast differentiation and TIMP-1 and TIMP-2 expression to an equivalent extentnas H2 relaxin (100 ng/mL), while also inhibiting Smad2 phosphorylation to approximately half the extent ofnH2 relaxin (all p < 0.05 vs TGF-β1). Lower doses of H3 (50 ng/mL) and H2 (50 ng/mL) relaxin additivelyninhibited TGF-β1-stimulated collagen deposition in vitro, while H3 relaxin was also found to reverse leftnventricular collagen overexpression in the model of fibrotic cardiomyopathy in vivo. These combined findingsndemonstrate that H3 relaxin exerts antifibrotic actions via RXFP1 and may enhance the collagen-inhibitoryneffects of H2 relaxin
机译：人类基因3（H3）松弛素是松弛素肽家族中最新发现的成员，并且可能与所有已定义的松弛素家族肽受体（RXFP1-4）结合。虽然通过其主要受体RXFP3越来越多地研究其作为厌氧调节剂的作用，其通过othernRXFP的动作知之甚少。因此，我们使用体外原发性大鼠RXFP1而非RXFP3的心室成纤维细胞和体内纤维化性心肌病的小鼠模型，具体确定了H3松弛素通过RXFP1受体的抗纤维化作用及其机制。向心室成纤维细胞施用转化生长因子β1（TGF-β1）显着增加Smad2磷酸化，成肌纤维细胞分化和胶原蛋白沉积（与未治疗的对照组相比，所有p <0.05），而对基质金属蛋白酶（MMP）9，MMP-13没有明显影响，金属蛋白酶（TIMP）1的组织抑制剂或TIMP-2表达持续72小时以上。 H3松弛素（分别为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的作用与相同剂量的H2松弛素相当。此外，H3松弛素（100 ng / mL）在同等程度上显着抑制TGF-β1刺激的心肌成纤维细胞分化以及TIMP-1和TIMP-2的表达； H2松弛素（100 ng / mL），同时也将Smad2磷酸化抑制约一半nH2松弛素的程度（相对于TGF-β1，所有p <0.05）。较低剂量的H3（50 ng / mL）和H2（50 ng / mL）的松弛素在体外可加成抑制TGF-β1刺激的胶原蛋白沉积，而在体内纤维化性心肌病模型中，还发现H3松弛素可逆转左室胶原过度表达。这些综合发现表明，H3松弛素可通过RXFP1发挥抗纤维化作用，并可能增强H2松弛素的胶原蛋白抑制作用

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