TNAP is a novel regulator of cardiac fibrosis after myocardial infarction by mediating TGF-β/Smads and ERK1/2 signaling pathways

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.