miRNAs Have Big Effects in the Heart

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Science  04 May 2007:
Vol. 316, Issue 5825, pp. 663
DOI: 10.1126/science.316.5825.663b

MicroRNAs (miRNAs) are important regulators of gene expression during development, through their ability to turn off the translation of targeted mRNAs. Two studies describe how miRNAs contribute to heart development and physiology {see also van Rooij et al., Science 316, 575 (2007)]. Yang et al. show that miR-1 abundance increases in patients with coronary heart disease and in rat models of cardiac infarction (heart attack), specifically in the ischemic area relative to the expression in the nonischemic area. Arrhythmias often occur after a heart attack and, in the rat model, delivery of an antisense oligonucleotide (which decreases the abundance of miR-1 in the myocardium) decreased postinfarct arrhythmias. Conversely, overexpression of miR-1 increased the occurrence of postinfarct arrhythmias and promoted arrhythmia in healthy hearts. The pathophysiology appeared to result from slowed conduction and depolarization of the heart, which were reversed by treatment with the miR-1 anti-sense oligonucleotide. Sequences complementary to miR-1 were present in the 3′-untranslated regions of the transcripts for the Kir2.1 subunit of the potassium channel, which is primarily responsible for setting the resting membrane potential, and for the connexin 43 gap junction protein. Indeed, these two proteins were less abundant in rats that had experienced myocardial infarction, and this drop was eliminated if the rats were treated with the antisense oligonucleotide to miR-1. To verify that these two proteins were responsible for the arrhythmias, each was knocked down by RNA interference, and this caused arrhythmias in ischemic hearts.

Zhao et al. examined the role of miR-1-2 in heart development and found that homozygous knockout mice showed an increased occurrence of death due to ventricular septal defects, which may have been the result of increased abundance of the transcription factor Hand2 (a key regulator of cardiac morphogenesis). Mice that survived exhibited cardiac hyperplasia due to an increased number of postnatal cells undergoing cell division. These mice also exhibited cardiac arrhythmias, which appeared to be due to altered potassium channel abundance as a consequence of increased abundance of the transcription factor Irx5 (a repressor of the potassium channel gene Kcnd2). — NRG

Nat. Med. 13, 486 (2007); Cell 129, 303 (2007).


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