Research Unit of Histology & Embryology, Dept. Experimental & Clinical Medicine, University of Florence, Viale G.Pieraccini 6, 50139 Florence, Italy.
Section of Anatomy & Histology, Dept. Experimental & Clinical Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy.
Mol Cell Endocrinol. 2018 Sep 5;472:80-86. doi: 10.1016/j.mce.2017.11.021. Epub 2017 Nov 24.
ADAM10 metalloprotease is required for activation of Notch-1, a transmembrane receptor regulating cell differentiation, proliferation and apoptosis, whose intracellular proteolytic fragment NICD mediates some key cardiovascular effects of the hormone relaxin (RLX). This study demonstrates the involvement of ADAM10 and PI3K/Akt signaling in mediating RLX-induced Notch-1 activation. H9c2 cardiomyocytes and NIH3T3 fibroblasts were incubated with human RLX-2 (17 nmol/l, 24 h) in presence or absence of the PI3K or Akt inhibitors wortmannin (WT, 100 nmol/l) and triciribine (TCN, 1 μmol/l). Cyclohexanedione-inactivated RLX (iRLX) served as negative control. RLX significantly increased Akt phosphorylation, ADAM10 and NICD expression, which were abolished by WT or TCN and did not occur with iRLX. These findings highlight a new receptor-specific signal transduction pathway of RLX.
ADAM10 金属蛋白酶对于 Notch-1 的激活是必需的，Notch-1 是一种调节细胞分化、增殖和凋亡的跨膜受体，其细胞内蛋白水解片段 NICD 介导了激素松弛素 (RLX) 的一些关键心血管效应。本研究表明 ADAM10 和 PI3K/Akt 信号通路参与了 RLX 诱导的 Notch-1 激活。在存在或不存在 PI3K 或 Akt 抑制剂wortmannin (WT，100nmol/l) 和 triciribine (TCN，1μmol/l) 的情况下，用人类 RLX-2(17nmol/l，24h)孵育 H9c2 心肌细胞和 NIH3T3 成纤维细胞。环己二酮失活的 RLX(iRLX) 作为阴性对照。RLX 显著增加了 Akt 磷酸化、ADAM10 和 NICD 的表达，而 WT 或 TCN 可消除这种作用，iRLX 则不会引起这种作用。这些发现强调了 RLX 的一种新的受体特异性信号转导途径。
