The Role of MicroRNA-133 in Cardiac Hypertrophy Uncovered

Abstract

See related article, pages 166–175 Studies of microRNAs (miRNAs) have recently uncovered a new level of intricacy in the regulation of gene expression during organogenesis and pathogenesis.1 miR-133, which is enriched in cardiac and skeletal muscle, is involved in cell specification,2 differentiation,3 and development.4 It is also downregulated during cardiac hypertrophy,5–7 which suggested that it may play a role in the underlying pathogenesis. Studies that included targeted deletion, overexpression, and antisense-specific knockdown of miR-133 have unraveled many aspects of its function and targets but have not directly revealed its role in the development of pressure overload–induced hypertrophy. In particular, targeted deletion of miR-133a-1 or miR-133a-2, each of which resulted in ≈50% reduction in cardiac miR-133, equivalent to the decrease associated with cardiac hypertrophy, exhibited no cardiac growth or functional abnormalities under normal or pressure overload conditions.4 On the other hand, complete ablation of miR-133 via double knockout resulted in aberrant proliferation and apoptosis of myocytes, cardiac defects, and prevalent embryonic lethality, whereas those that escaped the lethal phenotype ended with severe cardiac dilatation, but no myocyte hypertrophy.4 In contrast, knockdown of miR-133 via antisense targeting was sufficient for inducing cardiac hypertrophy and reinduction of the fetal gene program in the adult mouse heart.6 The discrepancy between the outcomes could be explained by the different onsets of …