Loss of Cardiac microRNA-Mediated Regulation Leads to Dilated Cardiomyopathy and Heart Failure

Abstract

RATIONALE Heart failure is a deadly and devastating disease that places immense costs on an aging society. In order to develop therapies aimed at rescuing the failing heart, it is important to understand the molecular mechanisms underlying cardiomyocyte structure and function. OBJECTIVE microRNAs are important regulators of gene expression and we sought to define the global contributions made by microRNAs toward maintaining cardiomyocyte integrity. METHODS AND RESULTS First, we performed deep sequencing analysis to catalog the miRNA population in the adult heart. Secondly, we genetically deleted, in cardiac myocytes, an essential component of the machinery that is required to generate miRNAs. Deep sequencing of miRNAs from the heart revealed the enrichment of a small number of microRNAs with one, miR-1, accounting for 40% of all microRNAs. Cardiomyocyte-specific deletion of dgcr8, a gene required for microRNA biogenesis, revealed a fully penetrant phenotype that begins with left ventricular malfunction progressing to a dilated cardiomyopathy and premature lethality. CONCLUSIONS These observations reveal a critical role for microRNAs in maintaining cardiac function in mature cardiomyocytes and raise the possibility that only a handful of microRNAs maybe ultimately be responsible for the dramatic cardiac phenotype seen in the absence of dgcr8.

DiGeorge Syndrome Critical Region 8 (DGCR8) Protein-mediated microRNA Biogenesis Is Essential for Vascular Smooth Muscle Cell Development in Mice

“…The left and right ventricles of the heart were enlarged, and the ventricular wall was thinner in DGCR8 cKO mice (supplemental Fig. 1, B-D), which are similar to the findings described in mice with cardiac-specific knockout of DGCR8 (16). These observations are similar to what is clinically observed in end-stage heart failure, suggesting that the cKO embryos developed a cardiomyopathy-like condition.…”

“…Of 670 mouse miRNA probes in the array, after filtering out miRNAs with low signals, 218 miRNAs had detectable signals. 171 showed significant down-regulation, 16 were not significantly altered, and 31 were up-regulated specifically in DGCR8 cKO umbilical arteries. The array results indicated that the loss of DGCR8 leads to a global down-regulation of miRNA expression.…”

Mammalian microRNAs: experimental evaluation of novel and previously annotated genes

“…RNA editing in which adenosine is deaminated and thereby converted to inosine (I) has been reported for (Rao et al 2009) and newborn are mapped to the mir-133a-1 hairpin (top), and data from the ectopic expression assay are mapped to the indicated transfected hairpin (bottom). The lines indicate miR-133a.1 (dark blue) and miR-133a.2 (light blue), and red nucleotides indicate those that differ between mir-133a-1 and mir-133a-2.…”

Eccentric and concentric cardiac hypertrophy induced by exercise training: microRNAs and molecular determinants

“…Several in vivo and in vitro studies have shown that miRs regulate a myriad of cellular processes, including heart development and cardiac hypertrophy, both under physiological and pathological conditions (50)(51)(52)(53). Some important issues have been highlighted regarding the participation of miR in the process of pathological cardiac hypertrophy, since many targets can be regulated simultaneously or synergistically by one or more miRs, and miRs also can be regulated by molecular bases involved in cardiac hypertrophy and other processes, reinforcing or attenuating its phenotype (53)(54)(55).…”

“…Nevertheless, there has been little investigation about miRs and physiological cardiac hypertrophy (51,57).…”