The microRNA-132/212 family fine-tunes multiple targets in Angiotensin II signalling in cardiac fibroblasts.

Abstract

MicroRNAs (miRNAs) are emerging as key regulators of cardiovascular development and disease; however, the cardiac miRNA target molecules are not well understood. We and others have described the Angiotensin II (AngII)-induced miR-132/212 family as novel regulators of cardiovascular function including regulation of cardiac hypertrophy, heart failure and blood pressure possibly through AT1R signalling. However, the miR-132/212 targets in the heart remain unknown. To understand the role of these miRNAs in cardiac signalling networks, we undertook comprehensive in silico and in vitro experiments to identify miR-132/212 molecular targets in primary rat cardiac fibroblasts. MiR-132/212 overexpression increased fibroblast cell size and mRNA arrays detected several hundred genes that were differentially expressed, including a wide panel of receptors, signalling molecules and transcription factors. Subsequent comprehensive in silico analysis identified 24 target genes, of which 22 genes were qPCR validated. We identified seven genes involved in AngII signalling pathways. We here report novel insight of an extensive network of molecular pathways that fine-tuned by miR-132/212, suggesting a role for this miRNA family as master signalling switches in cardiac fibroblasts. Our data underscore the potential for miRNA tools to manipulate a large array of molecules and thereby control biological function.