The role of microRNA-133 in cardiac hypertrophy uncovered.

Studies of microRNAs (miRNAs) have recently uncovered a new level of intricacy in the regulation of gene expression during organogenesis and pathogenesis.1 miR133, 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 miR-133 knockdown in the heart. However, none of the studies investigated the relevance of the decrease in miR-133 in the context of pressure overload hypertrophy. It should be noted that whereas overexpression or knockout of a gene in a normal cell can provide invaluable insight regarding its function, normalizing its levels during a specific pathological condition is requisite for obtaining direct evidence regarding its role in the underlying pathogenesis. Indeed, adopting this approach was one of the advantages of the study by Matkovich et al that is reported in this issue, in which they generated a transgenic mouse model overexpressing an -myosin heavy chain-regulated miR-133 gene.8 In contrast to a -myosin heavy chain-driven miR-133,4 these animals survived with no abnormalities other than a modest prolongation of the QT interval. The lack of more severe aberrations, which may have been expected from the suppression of some of the validated targets of miR-133 (Table), could be explained by the possibility that miR-133 under normal conditions is saturating with respect to some of its target mRNAs. However, the function of miR-133 was exposed after applying pressure overload to the miR-133 transgenic heart, a situation in which the overexpressed transgene compensated for the reduction in endogenous miR-133. Although cardiac weight was not normalized as a result of this intervention, other aspects of hypertrophy (including apoptosis, fibrosis, and the downregulation of IKr) were restored to baseline levels, whereas the decline in Ito,f and prolongation of QT interval were partly reversed. The decrease in fibrosis in the transgenic mouse could not be explained by suppression of connective tissue growth factor, which is a validated miR-133 target in cardiac myocytes and fibroblasts9; it is most likely a consequence of reduced myocyte dropout, infiltration, fibroblast proliferation, and The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark. Correspondence to Maha Abdellatif, Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103. E-mail [email protected] (Circ Res. 2010;106:16-18.) © 2009 American Heart Association, Inc.