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Original Article

Korean J Physiol Pharmacol 2022; 26(6): 469-478

Published online November 1, 2022

Copyright © Korean J Physiol Pharmacol.

The WNT/Ca2+ pathway promotes atrial natriuretic peptide secretion by activating protein kinase C/transforming growth factor-β activated kinase 1/activating transcription factor 2 signaling in isolated beating rat atria

Zhi-yu Li1,2,#, Ying Liu1,#, Zhuo-na Han1, Xiang Li1, Yue-ying Wang1, Xun Cui1,3,*, and Ying Zhang2,*

1Department of Physiology, School of Medicine, Yanbian University, 2Institue of Clinical Medicine, Yanbian University, 3Cellular Function Research Center, Yanbian University, Yanji 133-002, China

Correspondence to:Xun Cui
Ying Zhang

#These authors contributed equally to this work.

Author contributions: Z.Y.L. performed atrial perfused experiments. Y.L. and Z.N.H. performed WB analysis. X.L. and Y.Y.W. performed ANP measurement. X.C. and Y.Z. designed experiments and wrote the manuscript.

Received: April 18, 2022; Revised: July 16, 2022; Accepted: August 1, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


WNT signaling plays an important role in cardiac development, but abnormal activity is often associated with cardiac hypertrophy, myocardial infarction, remodeling, and heart failure. The effect of WNT signaling on regulation of atrial natriuretic peptide (ANP) secretion is unclear. Therefore, the purpose of this study was to investigate the effect of Wnt agonist 1 (Wnta1) on ANP secretion and mechanical dynamics in beating rat atria. Wnta1 treatment significantly increased atrial ANP secretion and pulse pressure; these effects were blocked by U73122, an antagonist of phospholipase C. U73122 also abolished the effects of Wnta1-mediated upregulation of protein kinase C (PKC) β and γ expression, and the PKC antagonist Go 6983 eliminated Wnta1-induced secretion of ANP. In addition, Wnta1 upregulated levels of phospho-transforming growth factor-β activated kinase 1 (p-TAK1), TAK1 banding 1 (TAB1) and phospho-activating transcription factor 2 (p-ATF2); these effects were blocked by both U73122 and Go 6983. Wnta1-induced ATF2 was abrogated by inhibition of TAK1. Furthermore, Wnta1 upregulated the expression of T cell factor (TCF) 3, TCF4, and lymphoid enhancer factor 1 (LEF1), and these effects were blocked by U73122 and Go 6983. Tak1 inhibition abolished the Wnta1-induced expression of TCF3, TCF4, and LEF1 and Wnta1-mediated ANP secretion and changes in mechanical dynamics. These results suggest that Wnta1 increased the secretion of ANP and mechanical dynamics in beating rat atria by activation of PKC–TAK1–ATF2–TCF3/LEF1 and TCF4/LEF1 signaling mainly via the WNT/Ca2+ pathway. It is also suggested that WNT–ANP signaling is implicated in cardiac physiology and pathophysiology.

Keywords: Activating transcription factor 2, Atrial natriuretic peptide, Protein kinase C, T cell factor and lymphoid enhancer factor, WNT signaling