Korean J Physiol Pharmacol.  2022 Nov;26(6):469-478. 10.4196/kjpp.2022.26.6.469.

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

• Li Zy
• Liu Y
• Han Zn
• Li X
• Wang Yy
• Cui X
• Zhang Y

• KMID: 2534523
• DOI: http://doi.org/10.4196/kjpp.2022.26.6.469

Abstract

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.

Keyword

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

Figure

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  Fig. 1 Effects of Wnt agonist 1 on atrial atrial natriuretic peptide (ANP) secretion (A) and dynamics (B) in beating rat atria. Data were expressed as means ± SE. n = 6. Cont, control; Wnta1, Wnt agonist 1; the collection time for each fraction is 2 min. *p < 0.05 vs. control.

• 

  Fig. 2 Effects of phospholipase C (PLC) antagonist on Wnt agonist 1-induced atrial natriuretic peptide (ANP) secretion (A) and dynamics (B) in beating rat atria. Data were expressed as means ± SE. n = 6. Cont, control; Wnta1, Wnt agonist 1; U, U73122; the collection time for each fraction is 2 min. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 3 Effects of Wnt agonist 1 on protein kinase C (PKC)β (A) and PKCγ (B) expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

• 

  Fig. 4 Effects of protein kinase C (PKC) antagonist on Wnt agonist 1-induced atrial natriuretic peptide (ANP) secretion (A) and dynamics (B) in beating rat atria. Data were expressed as means ± SE. n = 6. Cont, control; Wnta1, Wnt agonist 1; Go, Gö6983, an antagonist of PKC; the collection time for each fraction is 2 min. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 5 Effects of phospholipase C (PLC) (A) and protein kinase C (PKC) (B) antagonists on Wnt agonist 1-induced TAK1 banding 1 (TAB1) expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122; Go, Gö6983. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 6 Effects of phospholipase C (PLC) (A, B) and protein kinase C (PKC) (C, D) antagonists on Wnt agonist 1-induced TAK1 expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122; Go, Gö6983; p-TAK1, phospho-TAK1; t-TAK1, total-TAK1. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 7 Effects of phospholipase C (PLC) (A), protein kinase C (PKC) (B) and TAK1 (C) antagonists on Wnt agonist 1-induced ATF2 expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122; Go, Gö6983, TI, TAK1 inhibitor, an inhibitor of TAK1; p-ATF2, phospho-ATF2; t-ATF2, total-ATF2. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 8 Effects of phospholipase C (PLC), protein kinase C (PKC) and TAK1 antagonists on Wnt agonist 1-induced T cell factor (TCF)3 (A–C) and TCF4 (D–F) expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122; Go, Gö6983, TI, TAK1 inhibitor. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 9 Effects of phospholipase C (PLC) (A), protein kinase C (PKC) (B) and TAK1 (C) antagonists on Wnt agonist 1-induced lymphoid enhancer factor 1 (LEF1) expression in beating rat atria. Data were expressed as means ± SE. n = 5. Cont, control; Wnta1, Wnt agonist 1; U, U73122; Go, Gö6983, TI, TAK1 inhibitor. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 10 Effects of TAK1 antagonist on Wnt agonist 1-induced atrial natriuretic peptide (ANP) secretion (A) and dynamics (B) in beating rat atria. Data were expressed as means ± SE. n = 6. Cont, control; Wnta1, Wnt agonist 1; TI, TAK1 inhibitor. *p < 0.05 vs. control, #p < 0.05 vs. Wnta1.

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  Fig. 11 Schematic mechanisms by which Wnt agonist 1 (Wnta1) regulates atrial atrial natriuretic peptide (ANP) secretion and mechanical dynamics. PLC, phospholipase C; PKC, protein kinase C; TAB1, TAK1 banding 1; TCF, T cell factor; LEF1, lymphoid enhancer factor 1.

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