| BackgroudWith the aging of population structure in china,the incidence of atrial fibrillation(AF)increased gradually.And the risk of heart failure and systemic embolism in AF is high,which amplified with valvular heart disease(VHD).AF becomes an increasing burden for healthcare systems because of severe complications.Numerous theories tried to elucidate AF mechanisms,such as continuous AF drivers,multiple wavelet re-entry,remodeling of myocardial structure,complex fractionated atrial electrograms,and changes in calcium channel current.But the exact mechanisms were still incompletely understood.Calcineurin(CaN)has been reported to take part in cardiac hypertrophy.CaN is a Ca2+/calmodulin dependent protein phosphatase,which dephosphorylates(activates)Nuclear Factor of Activated T-cells(NFAT).The conformational changes promote NFAT translocation into nucleus and amplify hypertrophic gene program.In contrast,glycogen synthase kinase 3?(GSK3?)has been proved to negatively regulate cardiac hypertrophy.GSK3?phosphorylates(inactivates)NFAT and therefore increases their export from the nucleus,terminating the signal of hypertrophy.Protein kinase B(Akt/PKB)was a potent upstream regulator of GSK3?.Phosphorylation form of Akt(p-Akt,activated state)at Ser-473 has been identified to inhibit GSK3?(activated state)by phosphorylating it at Ser-9 as p-GSK3?(non-activated state),which terminated NFAT nuclear export.Recently,CaN-NFAT signaling pathway has been reported to involve in the pathogenesis of atrial fibrillation(AF).According to the underlying correlation of the two signaling pathways,we hypothesized Akt-GSK3? signaling pathway maybe also take part in the development of AF.However,data on Akt-GSK3p signaling pathway associated with the mechanism of valvular AF are limited,especially in human.Therefore this study was designed to investigate whether Akt-GSK3? signaling pathway participated in AF with VHD of human myocardium.Objective This study was designed to investigate whether Akt-GSK3p signaling pathwayparticipated in AF with VHD of human myocardium.MethodsStudy subjects included 42 adult patients with VHD undergoing open-heart surgery,who were divided into 2 groups based on heart rhythms:atrial fibrillation(AF)group(n=18);sinus rhythm(SR)group(n=24).We evaluated protein expression of CaN,total Akt,p-Akt,total GSK3p and p-GSK3? in human left atrial samples by Western Blot,with GAPDH as an internal reference.Physical and clinical data of patients were collected before operation.Results 1.Comparison among clinical data:There was no statistical difference concerning sex,age,body mass index(BMI),blood pressure(Bp)between two groups(all P>0.05).But heart rates and levels of plasm BNP were apparently higher in patients with AF compared to SR(all P<0.05).The course of disease in AF group was longer than SR group(P<0.05).2.Comparison among drug therapy:The rates of taking ?-Blockers and Digoxin with AF were significantly higher than patients with SR(all P<0.05).There was no difference among the other drugs(all P>0.05).3.Comparison among heart function:Heart function of AF group was even worse than SR group,which manifested as reduction of left ventricular ejection fraction(LVEF)(P<0.05).4.Comparison among the protein expressions of Akt-GSK3? and CaN:The protein expression levels of p-GSK3(3,total GSK3?,p-Akt were increased in AF group compared to SR(p-GSK3? 0.802±0.116vs0.482±0.076,P<0.001;total GSK3? 1.047±0.162vs0.703±0.109,P<0.001;p-Akt 1.027±0.126vs0.729±0.113,P<0.001).There was no statistical difference between the two groups about total Akt(1.074±0.089vs 1.028±0.0945,P=0.124).And the protein expression level of CaN was also elevated in AF group(1.097±0.153vs0.919±0.142,P<0.001).ConclusionAkt-GSK3? signaling pathway participated in the development of AF with VHD. |
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