Complement Upregulates Runx-2 to Induce Profibrogenic Change in Aortic Valve Interstitial Cells.
Complement Upregulates Runx-2 to Induce Profibrogenic Change in Aortic Valve Interstitial Cells.
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DOI：
10.1016/j.athoracsur.2020.12.058
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Jaggers J
中科院分区：
文献类型：
--
作者：
Deng XS;Meng X;Fullerton D;Stone M;Jaggers J
钙化性主动脉瓣病（CAVD）的主要发病机制是钙化和纤维化活动。在人狭窄主动脉瓣中观察到活性补体产物。Runt相关转录因子2（Runx-2）参与组织钙化。我们假设补体上调Runx-2诱导人主动脉瓣间质细胞（AVIC）的促纤维化变化。从6个正常和6个CAVD供体瓣膜中分离AVIC。用补体混合物处理细胞。通过蛋白质印迹分析和胶原染色分析促纤维化活性和相关信号分子。补体时间和剂量依赖性地增强AVIC中的促纤维化活性，并且补体暴露还诱导AVIC中的总胶原沉积。补体诱导的促纤维化反应与Runx-2表达增加和ERK 1/2磷酸化相关。Runx-2基因沉默降低MMP-9和胶原I水平。ERK 1/2的药理学抑制降低了人AVIC中补体介导的MMP-9、胶原I和Runx-2表达以及总胶原沉积。此外，与活性补体治疗相比，用热失活补体治疗AVIC导致MMP-9、胶原蛋白I和Runx-2水平降低。补体通过激活ERK 1/2介导的Runx-2信号通路诱导AVIC中的促纤维化活性。本研究证明了补体介导的CAVD发病机制的潜在作用，建立了限制CAVD进展的可能治疗靶点。
Calcium accumulation and fibrotic activities are principal mechanisms for calcific aortic valve disease (CAVD). Active complement products are observed in human stenotic aortic valves. Runt-related transcription factor 2 (Runx-2) is involved in tissue calcification. We hypothesized that complement up-regulates Runx-2 to induce pro-fibrogenic change in human aortic valve interstitial cells (AVICs). AVICs were isolated from 6 normal and 6 CAVD donor valves. Cells were treated with complement cocktails. Pro-fibrogenic activities and associated signaling molecules were analyzed by Western blot assay and collagen staining. Complement time and dose dependently enhanced pro-fibrogenic activities in AVICs, and complement exposure also induced total collagen deposition in AVICs. Complement induced pro-fibrogenic responses were associated with increased Runx-2 expression and phosphorylation of ERK1/2. Genetic silencing of Runx-2 decreased both MMP-9 and collagen I levels. Pharmacological inhibition of ERK1/2 decreased complement mediated MMP-9, collagen I and Runx-2 expression as well as total collagen deposition in human AVICs. Further, treating AVICs with heat-deactivated complement resulted in reduced MMP-9, collagen I and Runx-2 levels compared to active complement treatment. Complement induced pro-fibrogenic activities in AVICs by activation of ERK1/2 mediated Runx-2 signaling pathways. This study demonstrates a potential role for complement-mediated CAVD pathogenesis, establishing a possible therapeutic target to limit CAVD progression.
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DOI：
10.1161/circgenetics.115.001145
发表时间：
2015-12
期刊：
Circulation. Cardiovascular genetics
影响因子：
--
作者：
Guauque-Olarte S;Messika-Zeitoun D;Droit A;Lamontagne M;Tremblay-Marchand J;Lavoie-Charland E;Gaudreault N;Arsenault BJ;Dubé MP;Tardif JC;Body SC;Seidman JG;Boileau C;Mathieu P;Pibarot P;Bossé Y
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期刊：
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DOI：
10.1097/pai.0000000000000144
发表时间：
2016-02-01
影响因子：
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作者：
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