Effects Of Over-expression Of AdACE2on Ventricular Remodeling In Rat Model Of Myocardial Infarction

Objective:The aim of this study was to investigate the effect of over-expression ofangiotensin-converting enzyme2(ACE2) on ventricular remodeling in ratmodel of acute myocardial infarction (AMI) and the potential mechanisms.Methods:Male Sprague-Dawley rats (n=75) were randomly divided into fivegroups(each n=15): Sham operated group, AMI group, AMI+NormalSaline(AMI+NS group), AMI+Adenovirus-EGFP (AMI+AdEGFP group)and AMI+AdACE2group. AMI model were established by a ligation of theleft anterior descending coronary artery. Rats in the AMI+NS,AMI+AdEGFP and AMI+AdACE2groups received intramyocardialinjection of NS, AdEGFP and AdACE2, respectively. Rats in the AMI andSham groups received no injection intervention. Four weeks later, heartweight/body weight (HW/BW) was examined. Myocardial structurechanges and collagen deposition were evaluated histopathologically. Them-RNA expression of ACE2was evaluated by RT-PCR, and the expressionof AngII and Ang-(1-7) were assessed by immunohistochemical staining.The relative protein expression of ACE2, SHP-1, c-Src, p-c-Src, EGFR,p-EGFR, ERK1/2, p-ERK1/2, p38k, p-p38, TGF-β1andα-SMA weremeasured by western blotting. Results:(1) Compared with the other four groups, the mRNA and proteinexpression level of ACE2were significantly increasing in myocardial tissuein AMI+AdACE2group（P<0.05）.(2) In comparison with the AMI group,the level of heart weight(HW)/body weight (BW) and collagen depositionwere significantly decreased in myocardial tissue in AMI+AdACE2group.Compared with the sham group, immunohistochemical analysis showed thatthe expression level of AngⅡand Ang-(1-7) were upgraded in AMI、AMI+NS and AMI+AdEGFP group, and the expression of Ang-(1-7)seemed more significant in AMI+AdACE2group.(3) Western blottinganalysis showed that the expression levels of SHP-1was increased inAMI+AdEGFP group as compared with the other groups; the ratio ofp-c-Src/c-Src, p-EGFR/EGFR, p-ERK1/2/ERK1/2, p-p38/p38andα-SMA,TGF-β1protein expression were significantly decreased inAMI+AdACE2group.Conclusion:These results suggest that ACE2overexpression attenuated LV fibrosisand ameliorated LV remodeling, by up-regulating SHP-1expression andreducing phosphorylation of c-Src, EGFR, ERK1/2and p38, thus providinga potential therapeutic target in the treatment of heart failure.