Pathological Effects of Too Much or Too Little MicroRNA

Abstract

The short microRNAs have become well known for exerting important regulatory influences during development, including roles in heart development. Together, these two articles show a role for miRNAs in contributing to sudden death in the adult. Yang et al . show that miR-1 abundance is increased in patients with coronary heart disease and in rat models of cardiac infarction (heart attack). miR-1 expression is increased in the ischemic area relative to the expression in the nonischemic area (see Anderson and Mohler for commentary). Arrhythmias after a heart attack are common and, in the rat model, delivery of an antisense oligonucleotide to decrease miR-1 abundance in the myocardium decreased postinfarct arrhythmias, whereas overexpression of miR-1 increased the occurrence of postinfarct arrhythmias and was arrhythmogenic in healthy hearts as well. The arrhythmias appeared to result from slowed conduction and depolarization of the heart, which were reversed by treatment with the antisense oligonucleotide to miR-1 . Complementary sequences to miR-1 were present in the 3′-untranslated regions of the transcripts for the Kir2.1 subunit of the potassium channel, primarily responsible for setting the resting membrane potential, and for the connexin 43 gap junction protein. Indeed, these two proteins were decreased in abundance in rats that had experienced myocardial infarction, and this effect was eliminated if the rats were treated with the antisense oligonucleotide to miR-1 . Reporter gene experiments in transfected cultured cells and overexpression experiments in rat hearts confirmed that miR-1 targeted these two transcripts. 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 . returned to the developmental roles of miRNA in heart development and selectively knocked out miR-1-2 (see commentary by Mishima et al .). They found that homozygous mice showed an increased occurrence of sudden death or death due to failure of ventricular septation, which may have been the result of elevated abundance of the transcription factor Hand2, a key regulator of cardiac morphogenesis. Those mice that survived exhibited cardiac hyperplasia, which appeared to be due to increased numbers of postnatal cells undergoing cell division. The surviving mice also exhibited cardiac arrhythmias, which appeared to be due to altered potassium channel abundance as a consequence of elevated abundance of the transcription factor Irx5 that represses the expression of the potassium channel gene Kcnd2 . Because they had selectively knocked out one specific miRNA, the authors were able to analyze the targets of that miRNA. They determined that the complementary sites for miR-1-2 binding in the mRNAs that were increased in the knockout mouse hearts were in accessible regions of the mRNA (compared with the average calculated accessibility in any random mRNA pool). B. Yang, H. Lin, J. Xiao, Y. Lu, X. Luo, B. Li, Y. Zhang, C. Xu, Y. Bai, H. Wang, G. Chen, Z. Wang, The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2 . Nat. Med. 13 , 486-491 (2007). [PubMed] M. E. Anderson, P. J. Mohler, MicroRNA may have macro effect on sudden death. Nat. Med. 13 , 410-411 (2007). [PubMed] Y. Zhao, J. F. Ransom, A. Li, V. Vedantham, M. von Drehle, A. N. Muth, T. Tsuchihashi, M. T. McManus, R. J. Schwartz, D. Srivastava, Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129 , 303-317 (2007). [PubMed] Y. Mishima, C. Stahlhut, A. J. Giraldez, miR-1-2 gets to the heart of the matter. Cell 129 , 247-249 (2007). [PubMed]