Effect Of Wnt/Ca²⁺ Signaling Pathway On Atrial ANP Secretion

Objective:As one member of the family of cardiac natriuretic peptides,atrial natriuretic peptide(ANP)is involved in the regulation of body fluids and blood pressure homeostasis and possesses prevention of ischemia/reperfusion injury,anti-hypoxia,anti-inflammation,anti-oxidant,anti-proliferative,anti-hypertrophic and inhibition of Wnt signaling properties.Wnt signals transduction is an elaborate and complex aggregation of signaling pathways that regulates a wide range of cellular functions in development and adult,but abnormal in its activity often lead to developmental abnormalities and diseases,such as tumors,neurological,bone,and cardiovascular diseases.However,the effect of Wnt signaling on the regulation of ANP secretion is not clear.The purpose of this study,therefore,is to investigate the effect of Wnt agonist 1(Wnta)on ANP secretion and mechanical dynamics in isolated perfused beating rat atria.Methods:The isolated perfused beating rat atrial model was used and the measurement of ANP content in perfusates induced by radioimmunoassay.The proteins expression was determined by Western blot.Results:(1)Wnta(10?mol/L)significantly increased atrial ANP secretion and pulse pressure(P<0.05 vs.control period).The Wnta-induced increase in ANP secretion was completely blocked by U73122(15?mol/L),an antagonist of phospholipase C(PLC)(P<0.05 vs.Wnta period).The enhanced mechanical dynamics induced by Wnta was also blocked by U73122,even reversed its effect and presenting a negative inotropy(P<0.05 vs.control and Wnta period).(2)Wnta obviously upregualted expression of protein kinase C(PKC)?and?(P<0.05 vs.control group)and this was abolished by U73122(P<0.05 vs.control or Wnta group).Go6983(10?mol/L),an antagonist of PKC,eliminated the Wnta-induced secretion of ANP(P<0.05 vs.Wnta period).The atrial mechanical dynamics induced by Wnta was also repealed by Go6983,even reversed its effect and showed a negative inotropy(P<0.05 vs.control or Wnta period).(3)Wnta evidently upregulated the expression of transforming growth factor-?activated kinase 1(TAK1,P<0.05 vs.control group),this was blocked by U73122(P<0.05 vs.control or Wnta group)and also remarkably attenuated by Go6983(P<0.05 vs.control or Wnta group).(4)Wnta notably enhanced the expression of activating transcription factor 2(ATF2)(P<0.05 vs.control group),this was abrogated not only by U73122 and Go6983 but also by an inhibitor of TAK1(TAK1 inhibitor,TI;1?mol/L)(P<0.05 vs.Wnta group).(5)Wnta markedly upregulated expression of T cell factor(TCF)3/and TCF4/lymphoid enhancer factor 1(LEF1)(P<0.05 vs.control group)concomitantly with an increase in secretion of ANP and atrial mechanical dynamics(P<0.05 vs.control period),these effect were blocked by U73122 and Go6983(P<0.05 vs.Wnta group).The expression of TCF3,TCF4 and LEF1 were also abolished by TI(P<0.05vs.Wnta group)accompanied by a blocking of Wnta-induced ANP secretion and mechanical dynamics(P<0.05 vs.Wnta period).Conclusion:Wnta increased the secretion of ANP and mechanical dynamics by activation of PKC–TAK1–ATF2–TCF3/and TCF4/LEF1 signaling mainly via Wnt/Ca²⁺pathway in isolated beating rat atria.