Abstract

Role of microRNA-7 (miRNA-7) in targeting Epidermal growth factor receptor (EGFR/ERBB) family is known in dividing cancer cells while less is known about its role in terminally differentiated cardiac cells. We generated transgenic (Tg) mice with cardiomyocyte-specific overexpression of miRNA-7 to determine its role in regulating cardiac function. Despite similar survival, expression of miRNA-7 results in cardiac dilation as measured by echocardiography, instead of age-based cardiac hypertrophy observed in littermate controls. In contrast to the classical adaptive hypertrophy in response to TAC, miRNA-7 Tg mice directly undergo cardiac dilation post-TAC that is associated with increased fibrosis. Interestingly, significant loss in ERBB2 expression was observed in cardiomyocytes with no changes in ERBB1 (EGFR). Gene ontology and cellular component analysis using the cardiac proteomics data showed significant reduction in mitochondrial membrane integrity reflecting the differential enrichment/loss of proteins in miRNA-7 Tg mice compared to littermate controls. Consistently, electron microscopy showed that miRNA-7 Tg hearts had disorganized and rounded mitochondrial morphology indicating mitochondrial dysfunction. These findings show that expression of miRNA-7 uniquely results in cardiac dilation instead of adaptive hypertrophic response to cardiac stress providing insights on adverse remodeling in physiology and pathology.