激活NR1D1调节心力衰竭合并昼夜节律紊乱大鼠自主神经平衡并抑制心肌重构OA

AIM:To investigate the influence of nuclear receptor subfamily 1 group D member 1(NR1D1)ac-tivation on the autonomic nervous system in rats with heart failure and circadian rhythm disruption,as well as its potential therapeutic effects on myocardial remodeling,the following study was conducted.METHODS:Six-week-old male Dahl salt-sensitive(DS)rats were randomly allocated into four groups(n=10 per group):control group,high-salt diet(HSD)group,model group(HSD with circadian rhythm disruption)and agonist group(HSD with circadian rhythm disruption plus the NR1D1 agonist SR9009).Except for the control group,which received a normal diet,all rats were maintained on an HSD for a duration of 10 weeks.In the agonist group,after 6 weeks of high-salt diet feeding,the rats were intraperitone-ally injected with SR9009(100 mg·kg-1·d-1,once a day).Following 4 weeks of drug intervention,echocardiography was utilized to evaluate cardiac function.ECG signals in rats were recorded using an implantable wireless telemetry system,from which low-frequency(LF)and high-frequency(HF)power,as well as the LF/HF ratio,were calculated to assess heart rate variability.Histological analyses,including HE staining,Masson staining,wheat germ agglutinin(WGA)stain-ing,and immunohistochemistry were performed to analyze myocardial hypertrophy and fibrosis.Immunofluorescence stain-ing was employed to assess the expression of tyrosine hydroxylase(TH)and choline acetyltransferase(CHAT).Plasma norepinephrine(NE)levels were quantified via ELISA.Western blot or RT-qPCR was utilized to measure the expression of atrial natriuretic peptide(ANP),brain natriuretic peptide(BNP),β-myosin heavy chain(β-MHC),TH,CHAT,nerve growth factor(NGF),growth-associated protein-43(GAP43),NR1D1,and basic helix-loop-helix ARNT-like 1(BMAL1)in the left ventricular tissue.RESULTS:Compared with the control group,cardiac function was significantly impaired in the HSD group,accompanied by an increase in myocardial collagen fiber deposition(P<0.01)and elevated expression of myocardial hypertrophy markers(P<0.05 or P<0.01).The mRNA or protein expression levels of the sympa-thetic markers,including TH,NGF,GAP-43,and the circadian gene BMAL1 were upregulated,while NR1D1 and the parasympathetic marker CHAT were decreased(P<0.05 or P<0.01).Plasma NE levels were elevated(P<0.01),the LF component and the LF/HF ratio were increased(P<0.05 or P<0.01),and the HF component was decreased(P<0.01).Relative to the HSD group,cardiac function was further decreased in the model group,with exacerbated myocardial fibro-sis and hypertrophy(P<0.01).The expression levels of TH,NGF,GAP43,and BMAL1 were significantly elevated,while the expression of CHAT and NR1D1 was notably decreased(P<0.05 or P<0.01).Following NR1D1 activation,car-diac function was markedly improved,myocardial fibrosis and cellular hypertrophy were attenuated(P<0.01),BMAL1 expression was downregulated(P<0.01),and autonomic balance was effectively restored(P<0.05 or P<0.01).CON-CLUSION:Activation of NR1D1 regulates autonomic balance in rats with heart failure and circadian rhythm disruption,attenuates excessive sympathetic activation,enhances parasympathetic activity,and consequently inhibits myocardial re-modeling and slows the progression of heart failure.