| Gap junction(GJ),consisted of connexin(Cx),is the only channel of adjacent myocardial cells direct communication.In the heart,the mainly Cx are Cx40,Cx43,Cx45 etc.Cx40 is mainly in the atrium,atrioventricular node,bush’s beam,and ventricular conduction system;Cx43 mainly in atrium,ventricle and distal conduction system;while Cx45 mainly in the sinoatrial node,the atrioventricular node,beam and the bundle branch,less in atrium and ventricle.Study on hypertension hypertrophy and atrial fibrillation found,Cx remodeling was an important factor of atrial remodeling and electrical remodeling.A study in myocardial fibrosis old mice showed reduced the gene expression of Cx43 in ventricular muscle could increase the activation of fibroblast and myocardial fibrosis,presenting that resume the function of Cx43 could also be beneficial for the myocardial remodeling.In a variety of pathological conditions,the remodeling of Cx,consisted of the change of the expression,redistribution,abnormal combination and the disorder function of the channel etc,could decline the communication function of the GJ,slow the conduction velocity of atrial and inconsistent.So it was easy to form the turn-back and caused arrhythmia.Clinical studies have found that long-term hypertension not only lead to ventricular hypertrophy, expansion,even heart failure,also impact on atrial structure and function,including atrial expansion,fibrosis,atrial premature beat,flutter and atrial fibrillation.However,at present,research on hypertension focused on ventricular,lack of atrial and arrhythmias.As mentioned above,Cx remodeling is associated with hypertension ventricular remodeling,whether it play an equally important role in atrial remodeling remains to be elucidated.Therefore,this study observed the atrial structural changes in spontaneously hypertensive rats,detecting the function of atrial Cx,and signal transduction pathways.At the same time,clinical studies have shown that angiotensin converting enzyme inhibitors could prevent the occurrence of atrial fibrillation in patients with hypertension,and has been recommended in the clinical treatment guidelines,whether the role of the prevention of atrial fibrillation is association with Cx and inhibit atrial remodeling is still not clear,we also observed the effect of perindopril on the blood pressure of spontaneously hypertensive rats and atrial remodeling, to provide the basis for clinical treatment.Objective: To explore the role of Cx40 and Cx43 in the left atrial remodeling in hypertension and the effect of perindopril.Methods: Totally 12 SHR were randomly divided into two groups: Hypertension group(SHR group) and perindopril group(SHR-P group) and 6 Wistar rats were treated as normotensive control group(Wistar group).The rats in SHR-P group were treated with perindopril at the dose of 2mg/kg/d,the other rats were treated with distilled water,with measuring blood pressure once every two weeks.The echocardiography was taken respectively after adaptive feeding 1 week and 15 weeks.The level of Ang II in plasma was examined by kits.The changes of myocardial morphology were detected by HE staining.The gene expression of Cx40 and Cx43 were assayed by RT-PCR.The protein expression of Cx40, Cx43, JNK and p-JNK were assayed by Western-blot.Results:1 General conditionThe hair of the rats in SHR group were less and they were irritable.The rats in Wistar group had no the performances above.In the process of 15 weeks,there was no death in Wistar group,1 mouse was dead in SHR and 1 mouse was dead in SHR-P.2 The comparison of SBP among three groupsFrom 9 weeks, compared to the Wistar group, the SBP of tail artery of the rats in SHR group and SHR-P group were significantly higher(P<0.05). Compared to the SHR group,the SBP in SHR-P group were significantly lower(P<0.05)3 The comparison of echocardiography indexes among three groupsEchocardiography was taken in three groups at the start and the end of the study.At the start,there were no statistical significance of LAD、IVST、PWT、LVEDD、LVESD、LVEF and HR among different groups(P>0.05).At the end,the LAD value of the heart in Wistar group,SHR group and SHR-P group were 2.12±0.07 mm,2.99±0.12 mm and 2.72±0.25 mm,there were statistical significance among three groups(P<0.05).Compared to the Wistar group,the level of LAD in SHR group and SHR-P group was increased(P<0.05).Compared to the SHR group,the level of LAD in SHR-P group was decreased(P<0.05).The IVST value of the heart in Wistar group,SHR group and SHR-P group were 2.06±0.23 mm, 2.68±0.09 mm and 2.40±0.11 mm.The PWT value of the heart in Wistar group, SHR group and SHR-P group were 2.28±0.16 mm,2.76±0.28 mm and 2.44±0.10 mm,there were statistical signify- cance among three groups(P<0.05).Compared to the Wistar group,the level of IVST and PWT in SHR group and SHR-P group was increased(P<0.05). Compared to the SHR group,the level of IVST and PWT in SHR-P group was decreased(P<0.05).There were no statistical significance of LVEDD 、LVESD、LVEF and HR among different groups(P>0.05).4 The comparison of the level of Ang II in plasma among three groupsThe level of Ang II in plasma in Wistar group,SHR group and SHR-P group were 256±23.87ng/l,403.8±35.36 ng/l and 396.4±29.42ng/l,there were statistical significance among three groups(P<0.05).Compared to the Wistar group,the level of Ang II in plasma in SHR group and SHR-P group was increased(P<0.05).Compared to the SHR group,the level of Ang II in plasma in SHR-P group decreased(P<0.05).5 The changes of myocardial morphology by HE staining among three groupsWistar group: Myocardial cells were density,neat,inerratic, normomorph. The number and morphology of interstitial fibroblasts were normal.There were no significant pathological changes.SHR group:The volume and nucleus of myocardial cells increased,with concentrated dyeing cytoplasm.The order was loosely and disturbance,even with fibre fracture.There were a large number of fibers deposition in interstitial,dividing myocardial cells mesh shaped,with a small amount of inflammatory cells.SHR-P group:Compared to SHR group,the degree of the arrange of myocardial cells,the increasing of interstitial fibers and the arrange of interstitial fibers improved at a certain degree.6 The expression of Cx40 m RNA and Cx43 m RNA among three groupsCompared to the Wistar group,the level of Cx40 m RNA and Cx43 m RNA in SHR group and SHR-P group was decreased(P<0.05). Compared to the SHR group,the level of Cx40 m RNA and Cx43 m RNA in SHR-P group was increased(P<0.05)7 The expression of Cx40,Cx43,JNK and p-JNK among three groupsCompared to the Wistar group,the level of Cx40,Cx43,JNK and p-JNK in SHR group and SHR-P group was decreased(P<0.05).Compared to the SHR group,the level of Cx40,Cx43,JNK and p-JNK in SHR-P group was increased(P<0.05).Conclusions:1 In SHR group,the atrial of rats was significantly expanded,disordered arrangement of atrial muscle cells,fibrosis.It suggested hypertension lead to atrial remodeling.2 In SHR,the level of Cx40 and Cx43 in atrial muscle was decreased, and the level of JNK,p-JNK was increased.It suggested the change of Cx may be associated with atrial remodeling,and the activation of JNK signaling pathway had a role of adjust Cx function.3 In SHR, the level of Ang II in plasma was increased,and Ang II had a role of adjust JNK signaling pathway,so the inhibition of Ang II function may have the effect of the prevention of atrial remodeling.4 Compared to the SHR group, the atrium expansion degree is lighter, the level of Cx40 and Cx43 was higher, the concentration of Ang II in plasma, p-JNK was decreased in Perindopril group, suggested perindopril could lower the blood pressure,improve the atrial remodeling,its mechanism may be associated with Cx remodeling. |
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