MicroRNAs (miRNAs) are short (20-25 base pairs) RNA sequences that regulate gene expression. There are > 2500 miRNAs in the human genome, as listed in miRBase 20. MicroRNAs typically regulate a set of genes, often producing a functional response program,
1
and play a critical role in a range of cardiac remodelling paradigms, including myocardial infarction (MI),2
hypertrophy,3
heart failure,3
, 4
and atrial fibrillation.5
miRNAs (also abbreviated miRs) typically regulate their target gene by binding to the 3'-untranslated region of messenger RNA (mRNA) and preventing translation of the target mRNA to protein on the ribosome.1
miRNAs can also destabilize mRNA and cause its degradation, particularly when there is a high level of complementarity between the miRNA and its target mRNA. One important miRNA involved in cardiac development and dysfunction is miR-208a.6
The miR-208a coding sequence is embedded in an intronic (nontranslated) region of the MYH6 gene that encodes alpha-myosin heavy chain, the predominant heavy-chain contractile protein in the adult heart.7
Overexpression of miR-208a produces marked cardiac hypertrophy, downregulation of thyroid hormone-associated protein 1 (THRAP1) and myostatin (which negatively regulate cardiac hypertrophy and growth), contractile dysfunction, fibrosis, and arrhythmias; miR-208a knockout causes marked downregulation of beta-myosin heavy chain, a loss of connexin-40 (a cell-coupling hemichannel selectively expressed in atria and the conducting system), atrial conduction abnormalities and fibrillation, and dysregulation of transcription factors like homeobox-only protein (HOP).7
MiR-208a concentrations in circulating blood are greatly increased in acute MI,2
, 8
although any functional role in MI-related remodelling has been unclear.In the present issue of the Canadian Journal of Cardiology, Shyu et al.
9
report very interesting findings regarding miR-208a changes and their potential significance in rats with acute MI (MI rats). These authors noted a 3-fold increase in miR-208a expression in MI rats. MI rats developed left ventricular dysfunction and fibrosis, effects that were mimicked in sham rats by forced overexpression of miR-208a and were prevented in MI rats by overexpressing a specific miR-208a antagomir. Scrambled miR-208a sequences had no effect.The expression of endoglin was also increased in MI rats. Endoglin is an auxiliary transforming growth factor-β (TGF-β) receptor that modulates TGF-β1 and TGF-β3 responses, plays a crucial role in vascular function and repair,
10
and has known profibrotic effects.11
, 12
The authors hypothesized that miR-208a may affect MI-related remodelling by modulating endoglin expression, based on previous work that identified a region of the endoglin promoter with extensive complementarity to miR-208a.13
In the present study, they used a luciferase reporter attached to the endoglin promoter region (−700 to −1 from the transcriptional start site) to evaluate the direct regulation of endoglin gene expression by miR-208a. They report that both hypoxia and miR-208a enhanced endoglin promoter activity. Antagomir-208a or mutation of the miR-208a binding sites on the endoglin promoter abolished the stimulatory effect of miR-208a on the endoglin promoter. Antagomir-208a attenuated the endoglin promoter-enhancing effect of hypoxia, suggesting that miR-208a mediates the endoglin response to hypoxic conditions. Antagomir-208a also attenuated the endoglin-upregulating effect of acute MI, suggesting that it is mediated by miR-208a.The miR-208a regulation of endoglin described here is particularly interesting because it is one of a very small number of examples of direct gene upregulation by a miRNA, an anomalous form of regulation opposite the classic miRNA-induced gene silencing. The overwhelming majority of cases of direct miRNA-induced gene modulation involves downregulation by blocking protein translation.
1
, 2
However, in a limited number of cases, miRNAs directly enhance the expression of target proteins, generally by binding to the target-gene promoter and enhancing its transcription, a phenomenon that has been called “RNAactivation” or “RNAa.”14
The authors argue that acute MI enhances miR-208a expression, which activates endoglin transcription and thereby promotes adverse remodelling. They provide a proof of the principle that suppressing miR-208a action by administering an antagomir suppresses the endoglin upregulation and adverse remodelling resulting from acute MI. Mechanistic support for their reasoning is provided by a previous article showing that heterozygote endoglin knockout mice are protected against pressure-overload–induced mortality, myocardial dysfunction, and fibrosis.
15
One limitation of their argument is that their results do not prove that endoglin mediates the miR-208a role in adverse remodelling. It is possible that miR-208a upregulation after MI causes adverse remodelling through other mechanisms and also happens to cause upregulation of endoglin expression. Further work will be needed to establish without question the role of endoglin in the miR-208a effect.Nevertheless, Shyu et al.
9
have provided a wide range of novel and potentially important information: (1) that miR-208a can be upregulated by acute MI, (2) that endoglin expression is upregulated by acute MI, (3) that miR-208a overexpression can directly mimic adverse remodelling after MI, (4) that miR-208a knockdown can prevent adverse remodelling after MI, (5) that miR-208a knockdown suppresses endoglin upregulation after MI, and (6) that miR-208a directly and positively regulates endoglin transcription by binding to the endoglin gene promoter. These findings raise a host of new questions and therapeutic possibilities to be followed up in subsequent work, and they provide exciting mechanistic and translational leads toward the solution of the important clinical problem of adverse ventricular remodelling and functional impairment after acute MI.Funding Sources
Supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.
Disclosures
The author has no conflicts of interest to disclose.
References
- MicroRNAs in cardiovascular diseases: current knowledge and the road ahead.J Am Coll Cardiol. 2014; 63: 2177-2187
- MicroRNAs in myocardial infarction.Nat Rev Cardiol. 2015; 12: 135-142
- MicroRNAs in heart failure: is the picture becoming less miRky?.Circ Heart Fail. 2014; 7: 203-214
- Detailed characterization of microRNA changes in a canine heart failure model: relationship to arrhythmogenic structural remodeling.J Mol Cell Cardiol. 2014; 77: 113-124
- MicroRNAs and atrial fibrillation: mechanisms and translational potential.Nat Rev Cardiol. 2015; 12: 80-90
- The emerging role of miR-208a in the heart.DNA Cell Biol. 2013; 32: 8-12
- MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice.J Clin Invest. 2009; 119: 2772-2786
- Circulating microRNA: a novel potential biomarker for early diagnosis of acute myocardial infarction in humans.Eur Heart J. 2010; 31: 659-666
- MicroRNA-208a increases myocardial endoglin expression and myocardial fibrosis in acute myocardial infarction.Can J Cardiol. 2015; 31: 679-690
- The physiological role of endoglin in the cardiovascular system.Am J Physiol Heart Circ Physiol. 2010; 299: H959-H974
- Transforming growth factor-beta receptor endoglin is expressed in cardiac fibroblasts and modulates profibrogenic actions of angiotensin II.Circ Res. 2004; 95: 1167-1173
- Endoglin modulation of TGF-beta1-induced collagen synthesis is dependent on ERK1/2 MAPK activation.Cell Physiol Biochem. 2006; 18: 135-142
- Mechanical stretch via transforming growth factor-β1 activates microRNA208a to regulate endoglin expression in cultured rat cardiac myoblasts.Eur J Heart Fail. 2013; 15: 36-45
- Small RNA and transcriptional upregulation.Wiley Interdiscip Rev RNA. 2011; 2: 748-760
- Reduced endoglin activity limits cardiac fibrosis and improves survival in heart failure.Circulation. 2012; 125: 2728-2738
Article info
Publication history
Published online: March 14, 2015
Accepted:
March 11,
2015
Received:
March 11,
2015
Footnotes
See article by Shyu et al., pages 679-690 of this issue.
See page 592 for disclosure information.
Identification
Copyright
© 2015 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
