IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis
IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis
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DOI：
10.1093/cvr/cvy013
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发表时间：
2018-04-01
影响因子：
10.8
通讯作者：
Lin, Yen-Hung
中科院分区：
文献类型：
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作者：
Chou, Chia-Hung;Hung, Chi-Sheng;Lin, Yen-Hung
目的醛固酮过量导致心脏重构和纤维化。白细胞介素-6 （IL-6）是纤维化过程中的关键介质；然而，醛固酮对IL-6表达的影响尚不清楚。我们研究了醛固酮是否诱导IL-6的表达，从而促进了纤维化过程。方法与结果在本临床研究中，我们前瞻性地纳入了25例原发性醛固酮增多症（PA）患者和26例原发性高血压（EH）患者。与EH患者相比，PA患者血浆IL-6水平、左室质量指数、心肌纤维化程度较高，舒张功能受损更严重。此外，血浆IL-6水平与24小时尿醛固酮和超声心动图参数呈正相关。在细胞研究中，我们研究了醛固酮诱导IL-6分泌的可能分子机制以及胶原蛋白产生的进一步影响。醛固酮显著诱导人脐静脉内皮细胞产生IL-6蛋白和mRNA。细胞内信号通过矿皮质激素受体/PI3K/Akt/ nf - κ B通路发生。在心脏成纤维细胞中，IL-6反式信号传导在醛固酮诱导的IL-6增强的纤维化相关因子表达中起关键作用。为了进一步研究IL-6反式信号在醛固酮诱导的心肌纤维化中的作用，我们在醛固酮输注小鼠模型中测量了心肌纤维化的严重程度，包括IL-6化学抑制剂和Sgp130 Knockin转基因小鼠。小鼠接受重组可溶性gp130和Sgp130敲入转基因小鼠后，醛固酮输注可防止心肌纤维化和心肌肥厚。结论IL-6信号转导参与醛固酮诱导的心脏纤维化。
Aims An excess of aldosterone results in cardiac remodelling and fibrosis. Interleukin-6 (IL-6) is a key mediator in the fibrotic process; however, the effect of aldosterone on the expression of IL-6 remains unclear. We investigated whether aldosterone induces the expression of IL-6 and thereby contributes to the fibrotic process.Methods and results In this clinical study, we prospectively enrolled 25 patients with primary aldosteronism (PA) and 26 patients with essential hypertension (EH). The PA patients had higher plasma IL-6 levels, left ventricular mass index, degree of myocardial fibrosis, and more impaired diastolic function than the EH patients. In addition, plasma IL-6 levels were positively correlated with 24-h urinary aldosterone and echocardiographic parameters. In cell studies, we investigated the possible molecular mechanism how aldosterone-induced IL-6 secretion and the further effects of collagen production. Aldosterone significantly induced IL-6 protein and mRNA production in human umbilical vein endothelial cells. Intracellular signalling occurred through the mineralocorticoid receptor/PI3K/Akt/NF-kappa B pathway. In cardiac fibroblasts, IL-6 trans-signalling played a critical role in aldosterone-induced IL-6-enhanced fibrosis-related factor expression. To further investigate the role of IL-6 trans-signalling in aldosterone-induced cardiac fibrosis, we measured the severity of myocardial fibrosis in aldosterone infusion mice models including an IL-6 chemical inhibitor and Sgp130 Knockin Transgenic Mice. Mice receiving recombinant soluble gp130 and Sgp130 Knockin Transgenic Mice prevented myocardial fibrosis and cardiac hypertrophy by aldosterone infusion.Conclusions IL-6 trans-signalling contributes to aldosterone-induced cardiac fibrosis.