LAUSR

Cardiac injury is accompanied by dynamic changes in the expression of noncoding RNAs such as microRNAs (miRs) and long noncoding RNAs (lncRNAs) that regulate target genes. We previously reported that β 1 -adrenergic receptor/β-arrestin1-responsive miR-150 plays a vital cardioprotective role in myocardial infarction (MI) via decreasing cardiac cell apoptosis (Fig. A). MiR-150 is regulated by MI-Associated Transcript (MIAT), a lncRNA that directly interacts with miR-150 and functions as its competing endogenous RNA in vitro . Gain-of-function single nucleotide polymorphisms in MIAT are associated with increased risk of MI in humans, and MIAT is upregulated in post-MI hearts, concurrent with downregulation of miR-150. Despite the increasing data from both human and rodent studies, the conserved functional MIAT/miR-150 axis in cardiac pathology has never been investigated in genetically modified mice. Here, we hypothesize that MIAT competitively sequesters miR-150 and blocks the inhibitory effect of miR-150 on proapoptotic genes, thereby increasing maladaptive post-MI remodeling. Using novel mouse models, we demonstrate that global genetic deletion of MIAT in mice protects hearts against MI, while genetic overexpression of MIAT worsens maladaptive cardiac remodeling. Moreover, MIAT downregulates miR-150 in the heart, while miR-150 does not repress MIAT. Importantly, we show that miR-150 overexpression prevents the detrimental post-MI effects caused by overexpression of MIAT (Fig. B). In conclusion, these findings reveal a pivotal functional interaction between MIAT and miR-150 as a novel epigenetic regulatory mechanism pertinent to ischemic cardiac injury.