TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways
TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways
复制标题
TNAP 抑制通过停用 TGF-β1/Smads 和激活 P53 信号通路来减轻心肌梗塞引起的心脏纤维化。
DOI：
10.1038/s41419-020-2243-4
复制
发表时间：
2020-01-22
影响因子：
9
通讯作者：
Zhang, Dong-ying
中科院分区：
文献类型：
--
作者：
Gao, Lei;Wang, Li-you;Zhang, Dong-ying
组织非特异性碱性磷酸酶（TNAP）广泛表达于不同组织，调节代谢和炎症功能。然而，TNAP对心脏纤维化的影响仍然存在争议，需要进一步研究。本研究旨在探讨TNAP对心肌梗死（MI）后心肌纤维化的作用及其机制。TNAP在MI患者血清和受损心脏中均上调，并预测住院死亡率。TNAP在大鼠MI后也显著上调，主要在与胶原合成相结合的梗死心脏的边缘区。TNAP抑制剂四咪唑的给药显著改善了MI后的心功能和纤维化。在新生大鼠心脏成纤维细胞（CFs）的原代培养物中，TNAP抑制显著减弱了胶原相关基因的迁移、分化和表达。TGF-β 1/Smads信号转导通路受到抑制，p-AMPK和p53表达上调。当给予p53抑制剂时，TNAP抑制的抗纤维化作用可以被阻断。本研究为TNAP抑制剂可能是一种新的心肌纤维化调节剂提供了直接证据，并主要通过AMPK-TGF-β 1/Smads和p53信号发挥抗纤维化作用。
Tissue nonspecific alkaline phosphatase (TNAP) is expressed widely in different tissues, modulating functions of metabolism and inflammation. However, the effect of TNAP on cardiac fibrosis remains controversial and needs to be further studied. The present study aims to investigate the role of TNAP on myocardial infarction (MI)-induced fibrosis and its mechanism. TNAP was upregulated in patients with MI, both in serum and injured hearts, and predicted in-hospital mortality. TNAP was also significantly upregulated after MI in rats, mostly in the border zone of the infarcted hearts combined with collagen synthesis. Administration of TNAP inhibitor, tetramisole, markedly improved cardiac function and fibrosis after MI. In the primary cultures of neonatal rat cardiac fibroblasts (CFs), TNAP inhibition significantly attenuated migration, differentiation, and expression of collagen-related genes. The TGF-beta 1/Smads signaling suppression, and p-AMPK and p53 upregulation were involved in the process. When p53 inhibitor was administered, the antifibrotic effect of TNAP inhibition can be blocked. This study provides a direct evidence that inhibition of TNAP might be a novel regulator in cardiac fibrosis and exert an antifibrotic effect mainly through AMPK-TGF-beta 1/Smads and p53 signals.