Effect Of ACEI, ARB And Their Combination On The Myocardial Apoptosis And The Expression Of ACE2 After Myocardial Infarction In The Rat

Backgroud and Objectives: myocardial infarction causes lose of cardiac cells,myocyte hypertrophy in the non-infarcted zones,interstitial fibrosis,which ultimately lead to cardiac dysfunction.Myocardial apoptosis involved in cardiac remodeling,it produces continuous loss of cardiac cells after myocardial infarction.Both angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB) are proven to be effective in apoptosis inhibition and in improving ventricular remodeling,but the impact of ARB on myocardial infarction is still puzziled,and whether the combined use of ACEI and ARB is better than use them alone is also controversial.Otherwise many patients treated with an ACEI and/or ARB will still go on to have a myocardial infarction,whether this part of patients will still to profit on the use of RAS inhibitors is difficult to study in clinical trials. Angiotensin-converting enzyme 2 (ACE2) is a new found enzyme which is the homologue of ACE,ACE2 may plays a protective role to the heart,RAS and ACE2 may influence each other.But few researchs had been done to observe the change of ACE2 after myocardial infarction,so as to the impact of RAS inhibitors on it.There is no report on the relationship between ACE2 expression and myocardial apoptosis.Therefore,the purpose of this topic was to observe myocardial apoptosis after myocardial infarction, and to evaluate pretreatment with ACEI,ARB alone or in combination on the impact of myocardial apoptosis and its relationship with the ACE2 expression.Methods: Ninety Male Sprague-Dawley rats were randomly divided into five groups,n=18 in each group:(1)sham group,(2)myocardial infarction group(operation+isotonic Na chloride),(3)Telmisartan treated group (operation+telmisartan 1mg/kg.d), (4)fosinopril treated group(operation+fosinopril 10mg/kg.d),(5)combination treated group(operation+telmisartan 1mg/kg.d+fosinopril 10mg/kg.d).All drugs were orally given to AMI rats by gastric gavate once a day.After 14 days treatment, the AMI rat model was established by ligation of the left anterior desecending coronary artery,the Sham-operated rats underwent the same procedure except for the ligation.The follow-up points were at the first day and the 14th day after myocardial infarction.Hearts were collected after blood pressure measurement.Left ventricular mass index(LVMI)were caculated;to measure cardiomyocyte apoptosis,TUNEL staining(terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay)was performed according to the manufacturer's instruction; ACE2 protein expression of myocardium were semi-quantified by SP immunohistochemistry. ACE2mRNA were measured by Reverse Transcriptase Polymerase Chain Reaction (RT-RCR).Result:(1)Compared with AMI group,SBP,DBP,MBP of telmisartan,fosinopril treated groups were not changed,but the blood parameter was lower in the combination group.(2)LVMI was significantly increased in the AMI group at the 14th day after myocardial infarction,and it was significantly decreased by telmisartan , fosinopril and the combination treatment.(3)24h after myocardial infarction , the APOI markedly increased in the infracted areas and in the border zones(1.42%;2.37%) , but not in the remote non-infarcted myocardium(0.25%).(4)14d after myocardial infarction, the APOI in the infracted areas decreased and was no significantly different compare with the sham.The APOI markedly increased in the border zones(3.01%) and in the remote non-infarcted myocardium (0.74%).(5) 24h after myocardial infarction, telmisartan,fosinopril and combination pretreatment did not markedly decrease the APOI in the infracted areas and in the border zones though the APOI was lower in these groups.(6) 14d after myocardial infarction , in the border zones and in the remote nin-infarcted myocardium,telmisartan significantly decreased the APOI(2.20% vs 3.09% p<0.05;0.38% vs 0.74% p<0.05), so as to the fosinopril(2.25% vs 3.09% p<0.05;0.40% vs 0.74% p<0.05) ,the APOI in the combination group showed no significantly different compare with telmisartan,fosinopril.(7) 14d after myocardial infarction,compared with sham operated group,ACE2 protein increased significantly in infarcted group(p<0.05),telmisartan,fosinopril and combination therapy caused a significant increase in ACE2 protein expression compared with infarcted group (p<0.05),what's more ACE2 protein expression was significantly higher in the telmisartan group compare with the other two treated groups(p<0.05).(8)The ACE2 mRNA exprssion was not changed in the infracted group at the 14th day afther myocardial infarction,only telmisartan caused a significantly increase in ACE2 mRNA(p<0.05) though all therapied groups showed higher ACE2 mRNA expression.(9)14d after myocardial infarction,the linear correlation analysis suggested a significant negative correlation between APOI in the border zones and the ACE2 protein expression (r=-0.576,p<0.01),so as to the remote non-infarcted myocardium (r=-0.491,p<0.01).Conclusion: (1)Myocardial apoptosis occurs continuously after myocardial infarction.(2)Myocardial apoptosis can be alleviated coordinately by telmisartan,fosinopril and their combination therapy.The combination therapy is not better than telmisartan or fosinopril alone.(3)Telmisartan,fosinopril and their combination therapy can increase the expression of ACE2,telmisartan show a better effect on it.(4) ACE2 protein is associated with the decrease of myocardial apoptosis,it may take part in the mechanisms of the apoptosis inhibit effect of the RAS inhibitors.