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TNAP inhibition attenuates cardiac fibrosis induced by myocardial infarction through deactivating TGF-β1/Smads and activating P53 signaling pathways.
- Source :
-
Cell death & disease [Cell Death Dis] 2020 Jan 22; Vol. 11 (1), pp. 44. Date of Electronic Publication: 2020 Jan 22. - Publication Year :
- 2020
-
Abstract
- 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-β1/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-β1/Smads and p53 signals.
- Subjects :
- Adenylate Kinase metabolism
Alkaline Phosphatase antagonists & inhibitors
Alkaline Phosphatase blood
Alkaline Phosphatase genetics
Animals
Cell Differentiation
Cell Hypoxia drug effects
Collagen metabolism
Cyclin E metabolism
Fibroblasts pathology
Fibrosis
Hospital Mortality
Humans
Male
Membrane Proteins antagonists & inhibitors
Membrane Proteins blood
Membrane Proteins genetics
Myocardial Infarction blood
Myocardial Infarction mortality
Myocardial Infarction pathology
Myocardial Infarction physiopathology
Phosphorylation
Rats, Sprague-Dawley
Up-Regulation genetics
Vascular Remodeling
Alkaline Phosphatase metabolism
Membrane Proteins metabolism
Myocardium enzymology
Myocardium pathology
Signal Transduction
Smad Proteins metabolism
Transforming Growth Factor beta1 metabolism
Tumor Suppressor Protein p53 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 31969558
- Full Text :
- https://doi.org/10.1038/s41419-020-2243-4