| Objective:Neuregulin-1?NRG-1?plays a critical role in cardiac repair and regeneration in the infarction heart.The present study was designed to investigate the effect of NRG-1 on myocardial angiogenesis in rats with acute myocardial infarction,and the mechanisms involved.Methods:33 adult male SPF SD rats which were selected from the same source were randomly divided into three groups:Sham group?n=9?,AMI model group?n=12?and NRG group?n=12?.The rat models of myocardial infarction were established by ligation of the left anterior descending coronary artery in all groups except for sham group.The NRG groups were injected with dilutions of NRG-1?10ug/kg?during the first 2 hours of the model was established.The rats in Sham group or AMI model group were injected with an equivalent volume of saline,continuous intervention lasted for 7 days,then Analysis and collected samples,the samples include infarct region?IR?and peri-infarct region?PIR?.?1?All rats were detected by electrocardiogram before and after operation,and calculate the heart weight index of rats?heart weight/Body weight,HW/BW?.?2?After 7 days,heart function of the rats was measured by MPA cardiac function analysis system which include left ventricular systolic pressure?LVSP??Left ventricular end-diastolic pressure?LVEDP??maximum rate of left ventricular pressure rise and fall(±dp/dtmax).?3?Myocardial inflammation score was measured by HE staining.The myocardial collagen volume fraction?CVF?was observed by Masson staining.?4?capillary density was determined by the endothelial with cell marker CD31 and?-smooth muscle actin??-SMA?with Immunohistochemistry?IHC?staining.?5?The expression of angiogenesis related protein such as PI3K?AKT?P-AKT?eNOS?p-eNOS?VEGF?VEGFR2?Ang-1 and Ang-2 in myocardial tissues was measured by western blotting?WB??Results:?1?The model of rats with acute myocardial infarction is successful in AMI group and NRG group,No death in Sham group,3 deaths in AMI group,4 deaths in NRG group;There was no significant difference in heart rate between the three groups of rats before and after the operation.The heart weight index?HW/BW?of NRG group was higher than that of Sham group?P<0.05?.?2?Compared with the sham group,the indexes of left ventricular systolic pressure?LVSP?,left ventricular pressure rise maximum rate(+dp/dtmax),left ventricular pressure decrease maximum rate(-dp/dtmax)were decreased significantly,the indexes of left ventricular end diastolic pressure?LVEDP?were increased significantly?P<0.05 or P<0.01?in AMI group;Compared with AMI group,the indexes of LVSP and-dp/dtmaxax were increased significantly,the indexes of LVEDP was decreased significantly?P<0.05 or P<0.01?in NRG group.?3?HE staining showed that NRG group myocardial infarction morphology had improved compared with AMI group in infarct region and peri-infarct region;Masson staining showed that CVF in model group was significantly higher compared to the sham group?P<0.05?in infarct region and peri-infarct region,CVF in NRG group was significantly lower than that of AMI group?P<0.05?both in infarct region and peri-infarct region.?4?Compared with the Sham group,the capillary density of?-SMA+in the myocardial tissue of AMI group increased significantly?P<0.01?in the infarct region.The capillary density of CD31+and alpha-SMA+in the myocardial tissue of AMI group increased significantly?P<0.01?in the peri-infarct region.Compared with the AMI group,the capillary density of CD31+and?-SMA+in the myocardial tissue of NRG group increased significantly both in infarct region and peri-infarct region?P<0.05 or P<0.01?.?5?Compared with Sham group,the relative expression of PI3K?p-Akt?p-eNOS protein decreased significantly?P<0.05 or P<0.01?,the relative expression of VEGFVEGFR2and Ang-2 increased significantly?P<0.05 or P<0.01?in the myocardial tissue of AMI group both in infarct and peri-infarct region.Compared with AMI group,the relative expression of PI3K?p-Akt?p-eNOS?VEGF?VEGFR2?Ang-2protein increased significantly?P<0.05 or P<0.01?both in infarct and peri-infarct region.But,the expression of Ang-1 in three groups have no significantly differences.Conclusions:?1?NRG-1 can reduce myocardial injury and myocardial fibrosis after myocardial infarction in rats and protect the cardiac function.?2?NRG-1 can promote angiogenesis in rats with myocardial infarction.?3?The mechanism of NRG-1 promote angiogenesis may be related to activation of PI3K-Akt-eNOS?VEGF/VEGFR2 signaling pathways and the up-regulation of expression of Ang-2?... |
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