The Research Of β₁ Adrenergic Receptor、PI3K/AKT Pathway In The Progress Of Heart Failure Induced By Hypothyroidism In Rats

Objective: Hypothyroidism may lead to the dysfunction of the heart,eventually develop to heart failure.This research aims to show light on the underlying effect of β₁ adrenergic receptor（β₁-AR）and PI3K/AKT pathway in the process of heart failure,through assessing the noradrenaline（NE）changes in hypothyroidism induced heart failure rats,to explore the effect of β₁ adrenergic receptor and PI3K/AKT pathway in the progress of heart failure induced by hypothyroidism in rats,to identify the properly molecular mechanisms underlying the heart failure induced by hypothyroidism in rats.Methods: We use already confirmed heart failure rats model with hypothyroidism induced by 131 I,including normal group,100μCi group,300μCi group,500μCi group.ELISA kits was performed to analysis serum TT3,TT4,thyroid stimulating hormone（TSH）,B-type natriuretic peptide（BNP）and NE levels,cardiac ultrasound was performed to analysis the cardiac function.RT-PCR were used to analysis the expression of transcripts of β₁ adrenergic receptor 、 β₁ adrenergic receptor kinase（β₁-ARK）、Phosphoinositide 3-kinase（PI3K）、AKT（also known an protein kinase B）.Western Blot was performed to evaluate the protein expression levels of cardiac β₁-AR、PI3K、AKT、p-AKT.Results:1 Thyroid function of ratsAfter 4 weeks and 8 weeks treated by 131 I,the level of TT3,TT4 were decreased in the intervention groups（P<0.05）.Compared with normal group,the level of TSH was significantly increased in the intervention groups（P<0.05）.With the increase of dose,the difference was more significant.2 The Serum level of BNPAt 4th week,no significant difference of the level of BNP was observed in the intervention groups and the normal group（P > 0.05）.At 8th week,compared with normal group,the level of BNP in intervention groups showed significant difference（P<0.05）.With the increase of dose,the difference was more significant.3 Cardiac function of ratsAt 4th week,compared with normal control group interventricular septal（IVS）thickness was significantly increased in the treatment group（P<0.05）.Compared with normal control group,100μCi group,300μCi group,500μCi group,left ventricular end-diastolic dimension（LVEDD）of 700μCi group,900μCi group,1100μCi group showed significant difference（P<0.05）.Compared with normal control group and 100μCi group,left ventriculus postterior wall dimension（LVPWD）and ejection fraction（EF）of 300μCi,500μCi,700μCi,900μCi,1100μCi group showed significant difference（P<0.05）.Compared with normal control group,100μCi and 300μCi group,left ventricular end-systolic dimension（LVESD）of 500μCi,700μCi,900μCi,1100μCi group showed significant difference（P < 0.05）.Fractional shortening（FS）were decreased in the treatment group（P<0.05）.At 8th week,IVS,LVPWD of treatment group rats were increased（P<0.05）.Compared with normal control group and 100μCi group,LVEDD,LVESD,EF,FS of 300μCi,500μCi,700μCi,900μCi,1100μCi group showed significant difference（P<0.05）.With the increase of dose,the difference was more significant,but compared with the 300μCi and 500μCi group 700μCi,900μCi,1100μCi group had no significant difference.4 The Serum level of NEAt 8th week,compared with normal group,the level of NE of intervention group showed significant difference（P<0.05）,especially the 300μCi and 500μCi group;on the other hand,compared with 100μCi group,the increasing of NE in 300μCi and 500μCi group showed significant difference（P<0.05）.5 The expression of RNA in rats myocardial tissue gene after 8 weeks feeding:Compared with normal group,RT-PCR showed the increasing RNA expression of β₁-AR in each intervention groups with significant difference（P<0.05）,β₁-ARK showed the same difference in the 500μCi group（P<0.05）,PI3 K and AKT existed an significant increasing in 300μCi group and 500μCi group（P>0.05）.Compared with 100μCi group,expression of β₁-AR、PI3K、AKT showed an increasing in 500μCi group,and there was an increasing of PI3 K in 300μCi group,all the data shows significant difference.6 The protein expression of rats myocardial tissue protein after 8 weeks feeding:Western blot showed significant increasement of protein levels of β₁-AR、PI3K in the 300μCi and 500μCi group（P<0.05）,p-AKT in the 500μCi group（P<0.05）.No significant changes of AKT protein expression were observed in the all intervention groups（P>0.05）.All the indexes were found significant difference between 500μCi group and 100μCi group（P>0.05）.Conclusions:1 In the animal model of hypothyroidism induced heart failure rats,NE levels increased significantly,which indicated that the level of Catecholamines was rising.Therefore,Catecholamines maybe involved in the development of heart failure in hypothyroidism rats.2 In the animal model of hypothyroidism induced heart failure rats,compared with the normal group,β₁-AR、β₁-ARK、PI3K、AKT mRNA levels and protein levels increased significantly,which indicated that the β₁-AR 、 PI3K/AKT pathway was activated in the animal model of hypothyroidism induced heart failure rats,which underlied the progress of hypothyroidism induced heart failure.