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Analysis of changes in gene expression is an important means to define molecular differences associated with the phenotypic changes observed in response to myocardial infarction (MI). Several studies in humans or animal models have reported differential miRNA expression in response to MI acutely (animal) or chronically (human). To determine the relative contribution of microRNA (miRNA) and mRNAs to acute and chronic temporal changes in response to MI, mRNA and miRNA expression profiles were performed in three time points post-MI. Changes in mRNA and miRNA expression was analyzed by arrays and confirmed by RT-PCR. Bioinformatic analysis demonstrated that several genes and miRNAs in various pathways are regulated in a temporal or phenotype-specific manner. Furthermore miRNA analyses indicated that miRNAs can target expression of several genes involved in multiple cardiomyopathy-related pathways. Our results suggest that: 1) Differentially regulated miRNAs are predicted to target expression of several genes in multiple biological processes involved in the response to MI; 2) antithetical and compensatory changes in miRNA expression are observed at later disease stages, including antithetical regulation of miR-29, which correlates with the expression of collagen genes, and upregulation of apoptosis-related miRNAs at early stages and antiapoptotic/growth promoting miRNAs at later stages; 3) temporally dependent changes in miRNA and mRNA expression post-MI are generally characterized by dramatic changes acutely postinjury and are normalized as disease progresses; 4) A combinatorial analysis of mRNA and miRNA expression may aid in determining factors involved in compensatory and decompensated responses to cardiac injury.