Several recent reports have suggested that microRNAs (miRNAs) might play 
critical roles in acute myocardial infarction (AMI). However, the miRNA 
expression signature in the early phase of AMI has not been identified. In this 
study, the miRNA expression signature was investigated in rat hearts 6 h after 
AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs 
were differentially expressed in infarcted areas and 33 miRNAs were aberrantly 
expressed in the border areas. Remarkably, miR-21 expression was significantly 
down-regulated in infarcted areas, but was up-regulated in border areas. The 
down-regulation of miR-21 in the infarcted areas was inhibited by ischemic 
preconditioning, a known cardiac protective method. Overexpression of miR-21 via 
adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 
29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. 
Using both gain-of-function and loss-of-function approaches in cultured cardiac 
myocytes, we identified that miR-21 had a protective effect on ischemia-induced 
cell apoptosis that was associated with its target gene programmed cell death 4 
and activator protein 1 pathway. The protective effect of miR-21 against 
ischemia-induced cardiac myocyte damage was further confirmed in vivo by 
decreased cell apoptosis in the border and infarcted areas of the infarcted rat 
hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as 
miR-21 may play critical roles in the early phase of AMI.