Inhibition of leptin-induced vascular extracellular matrix remodelling by adiponectin.
Inhibition of leptin-induced vascular extracellular matrix remodelling by adiponectin.
复制标题
脂联素抑制瘦素诱导的血管细胞外基质重塑。
DOI：
10.1530/jme-14-0027
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发表时间：
2014-10
影响因子：
3.5
通讯作者：
Dai QY
中科院分区：
文献类型：
--
作者：
Zhang Z;Wang F;Wang BJ;Chu G;Cao Q;Sun BG;Dai QY
血管细胞外基质（ECM）重塑是ECM合成和降解平衡破坏的结果，诱导血管纤维化，从而导致高血压。已知瘦素促进组织纤维化，而脂联素最近已被证明在组织纤维化中具有抗纤维化作用。在这项研究中，我们的目的是评估脂联素的瘦素拮抗剂功能，并进一步阐明脂联素通过其抑制血管平滑肌细胞中瘦素信号传导的机制，从而防止在我们已经建立的3D共培养血管模型中产生过量的ECM。我们的3D共培养血管模型模拟真实血管，由血管内皮细胞、血管平滑肌细胞和I型胶原蛋白组成。我们验证了瘦素的促纤维化作用，并在3D血管模型中分析了基质金属蛋白酶2（MMP 2）、MMP 9、金属蛋白酶组织抑制剂1（TIMP 1）和II/IV型胶原的分泌。通过RNAi技术抑制内皮细胞中脂联素受体1（AdipoR）和AdipoR 2的表达，重新分析脂联素的保护/抑制作用。在3D血管模型中，脂联素阻断瘦素刺激的II/IV型胶原和TIMP 1的分泌，同时显著增加MMP 2/9活性。在内皮细胞中，脂联素诱导AMPK磷酸化，从而通过诱导平滑肌细胞中的SOCS 3抑制瘦素介导的STAT 3磷酸化。我们的研究结果表明，脂联素通过AdipoR 1破坏瘦素诱导的血管ECM重塑，并增强内皮细胞中的AMPK信号传导，这反过来又促进平滑肌细胞中SOCS 3的上调，从而抑制瘦素刺激的STAT 3磷酸化。
Vascular extracellular matrix (ECM) remodelling, which is the result of disruption in the balance of ECM synthesis and degradation, induces vessel fibrosis and thereby leads to hypertension. Leptin is known to promote tissue fibrosis, while adiponectin has recently been demonstrated to be anti-fibrogenic in tissue fibrosis. In this study, we aimed to evaluate the leptin-antagonist function of adiponectin and to further elucidate the mechanisms through which adiponectin dampens leptin signalling in vascular smooth muscle cells, thus preventing excess ECM production, in our already established 3D co-culture vessel models. Our 3D co-culture vessel model, which mimics true blood vessels, is composed of vascular endothelial cells, vascular smooth muscle cells and collagen type I. We validated the profibrogenic effects of leptin and analysed matrix metalloproteinase 2 (MMP2), MMP9, tissue inhibitor of metalloproteinase 1 (TIMP1) and collagen types II/IV secretion in 3D vessel models. The protective/inhibitory effects of adiponectin were re-analysed by inhibiting adiponectin receptor 1 (AdipoR) and AdipoR2 expression in endothelial cells using RNAi technology. In the 3D vessel models, adiponectin blocked the leptin-stimulated secretion of collagen types II/IV and TIMP1 while significantly increasing MMP2/9 activity. In endothelial cells, adiponectin induced phosphorylation of AMPK, thereby suppressing leptin-mediated STAT3 phosphorylation through induction of SOCS3 in smooth muscle cells. Our findings indicate that adiponectin disrupted the leptin-induced vascular ECM remodelling via AdipoR1 and enhanced AMPK signalling in endothelial cells, which, in turn, promoted SOCS3 up-regulation in smooth muscle cells to repress leptin-stimulated phosphorylation of STAT3.