TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways
TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways
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TNAP 是心肌梗死后心脏纤维化的新型调节剂，通过介导 TGF-b/Smads 和 ERK1/2 信号通路
DOI：
10.1016/j.ebiom.2021.103370
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发表时间：
2021-05-07
期刊：
影响因子：
11.1
通讯作者：
Zhang, Dongying
中科院分区：
文献类型：
--
作者：
Cheng, Xiaocheng;Wang, Liyou;Zhang, Dongying
背景：心脏纤维化是导致心肌梗死（MI）后心脏重塑和心力衰竭的最重要发病机制。组织非特异性碱性磷酸酶（TNAP）最近被认为是MI的潜在预后因素。然而，TNAP在心肌纤维化后MI的作用还没有明确划定。方法：进行系统回顾和荟萃分析，以评估血清TNAP水平对缺血性心脏病（IHD）患者死亡率的影响。进行相关性分析以研究血清TNAP水平与纤维化生物标志物之间的关系。采用心肌梗死患者和心肌梗死小鼠模型的心脏活检组织检测TNAP的表达和分布。此外，我们建立了腺病毒介导的敲低和过表达TNAP，在小鼠体内和体外研究的组合，以确定心肌梗死后心脏纤维化的作用和机制TNAP。在体外研究中，心脏成纤维细胞培养在软plates.Findings：在搜索主要数据库，并进行了详细的评估的全文文章，8项研究，14,816人被纳入定量分析。我们发现高血清TNAP水平与IHD和MI患者死亡风险增加相关。相关性分析显示血清TNAP水平与纤维化生物标志物（PICP/PIIINP）浓度之间呈正相关。TNAP的表达在MI患者的心肌和MI小鼠模型中上调，伴有成纤维细胞活化和胶原纤维沉积。在体内研究中，TNAP敲低改善了小鼠的心脏纤维化并改善了心脏功能。TNAP过度表达加重了心脏纤维化，恶化了心功能。在体外研究中，TNAP促进心脏成纤维细胞分化、迁移和增殖。从机制上讲，TNAP对心脏成纤维细胞的促纤维化作用至少部分是通过激活TGF-β 1/Smads和ERK 1/2信号通路实现的。解释：基于这些发现，TNAP通过激活TGF-β 1/Smads和ERK 1/2信号通路在MI后的心脏纤维化中起重要的促纤维化作用，表明它在心脏纤维化中起着潜在的调节剂和治疗靶点的作用。(C)2021年，任作者。由爱思唯尔公司出版
Background: Cardiac fibrosis is the most important pathogenesis leading to cardiac remodeling and heart failure after myocardial infarction (MI). Tissue nonspecific alkaline phosphatase (TNAP) has recently been recognized as a potential prognostic factor for MI. Nevertheless, the role of TNAP in cardiac fibrosis after MI has not been explicitly delineated.Methods: A systematic review and meta-analysis was conducted to assess the effect of serum TNAP levels on mortality in patients with ischemic heart disease (IHD). A correlation analysis was performed to investigate the relationship between serum levels of TNAP and biomarkers of fibrosis. Heart biopsies from patients with MI and a mouse model of MI were used to detect the expression and distribution of TNAP. Furthermore, we established adenovirus-mediated knockdown and overexpression of TNAP, using a combination of in vivo and in vitro studies in mice, to determine the role and mechanism of TNAP in cardiac fibrosis after MI. In the in vitro studies, cardiac fibroblasts were cultured on soft plates.Findings: After searching the main databases and performing a detailed assessment of the full-text articles, eight studies with 14,816 individuals were included in the quantitative analysis. We found that a high serum TNAP level was associated with an increased risk of mortality in patients with IHD and MI. The correlation analysis revealed a positive correlation between serum TNAP levels and the concentration of fibrosis biomarkers (PICP/PIIINP). The expression of TNAP was upregulated in the myocardium of patients with MI and in a mouse model of MI, accompanied by fibroblast activation and the deposition of collagen fibers. In the in vivo study, TNAP knockdown ameliorated cardiac fibrosis and improved cardiac function in mice. TNAP overexpression aggravated cardiac fibrosis and worsened cardiac function. In the in vitro study, TNAP promoted cardiac fibroblast differentiation, migration and proliferation. Mechanistically, the pro-fibrotic effect of TNAP on cardiac fibroblasts was at least partially achieved by activating the TGF-beta 1/Smads and ERK1/2 signaling pathways.Interpretation: Based on these findings, TNAP plays an important pro-fibrotic role in cardiac fibrosis after MI by activating TGF-beta/Smads and ERK1/2 signaling, indicating that it functions as a potential regulator of and therapeutic target in cardiac fibrosis. (C) 2021 The Author(s). Published by Elsevier B.V.