Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
Department of Cardiology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China; The Second Ward of Cardiovascular Medicine Department, Ankang City Central Hospital, Ankang, China.
EBioMedicine. 2021 May;67:103370. doi: 10.1016/j.ebiom.2021.103370. Epub 2021 May 7.
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.
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.
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-β1/Smads and ERK1/2 signaling pathways.
Based on these findings, TNAP plays an important pro-fibrotic role in cardiac fibrosis after MI by activating TGF-β/Smads and ERK1/2 signaling, indicating that it functions as a potential regulator of and therapeutic target in cardiac fibrosis.
This work was supported by the National Natural Science Foundation of China.
心肌纤维化是导致心肌梗死后心脏重构和心力衰竭的最重要的发病机制。组织非特异性碱性磷酸酶（TNAP）最近被认为是心肌梗死后的一个潜在预后因素。然而，TNAP 在心肌梗死后心肌纤维化中的作用尚未明确阐述。
进行了系统评价和荟萃分析，以评估血清 TNAP 水平对缺血性心脏病（IHD）患者死亡率的影响。进行了相关性分析，以研究血清 TNAP 水平与纤维化生物标志物之间的关系。使用 MI 患者的心脏活检和 MI 小鼠模型来检测 TNAP 的表达和分布。此外，我们使用体内和体外研究相结合的方法，在小鼠中建立了腺病毒介导的 TNAP 敲低和过表达，以确定 TNAP 在 MI 后心肌纤维化中的作用和机制。在体外研究中，将心脏成纤维细胞培养在软平板上。
在搜索主要数据库并对全文文章进行详细评估后，纳入了八项研究，共纳入 14816 名个体进行定量分析。我们发现，高血清 TNAP 水平与 IHD 和 MI 患者的死亡风险增加相关。相关性分析显示，血清 TNAP 水平与纤维化生物标志物（PICP/PIIINP）浓度呈正相关。TNAP 在 MI 患者的心肌和 MI 小鼠模型中表达上调，伴随着成纤维细胞激活和胶原纤维沉积。在体内研究中，TNAP 敲低改善了小鼠的心肌纤维化和心脏功能。TNAP 过表达加重了心肌纤维化并恶化了心脏功能。在体外研究中，TNAP 促进了心脏成纤维细胞的分化、迁移和增殖。在机制上，TNAP 通过激活 TGF-β1/Smads 和 ERK1/2 信号通路，对心脏成纤维细胞发挥至少部分促纤维化作用。
基于这些发现，TNAP 通过激活 TGF-β/Smads 和 ERK1/2 信号通路在 MI 后心肌纤维化中发挥重要的促纤维化作用，表明它作为心肌纤维化的潜在调节剂和治疗靶点。
本工作得到了国家自然科学基金的支持。
