MicroRNA-146a as a Regulator of Cardiac Energy Metabolism.

Abstract

HomeCirculationVol. 136, No. 8MicroRNA-146a as a Regulator of Cardiac Energy Metabolism Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBMicroRNA-146a as a Regulator of Cardiac Energy Metabolism Charlotte J. Demkes, MSc and Eva van Rooij, PhD Charlotte J. DemkesCharlotte J. Demkes From Hubrecht Institute, KNAW and University Medical Center Utrecht, The Netherlands (C.J.D., E.v.R.); and Department of Cardiology. University Medical Center Utrecht, The Netherlands (C.J.D., E.v.R.). Search for more papers by this author and Eva van RooijEva van Rooij From Hubrecht Institute, KNAW and University Medical Center Utrecht, The Netherlands (C.J.D., E.v.R.); and Department of Cardiology. University Medical Center Utrecht, The Netherlands (C.J.D., E.v.R.). Search for more papers by this author Originally published22 Aug 2017https://doi.org/10.1161/CIRCULATIONAHA.117.029703Circulation. 2017;136:762–764Article, see p 747The heart has a high mitochondrial content to generate the vast amount of ATP that is needed to provide the energy that is required for the continuous mechanical workload. Cellular ATP is predominantly used to support the contraction-relaxation cycle within the myocardium. Although cardiac mitochondria are flexible in using substrates to generate energy, the conversion of free fatty acids and glucose accounts for most of the ATP production in the healthy adult heart.1 However, during advanced stages of heart failure there is an imbalance between energy demand and availability, accompanied by a downregulation of fatty acid oxidation and an increase in glycolysis.2 Glucose becomes an important preferential substrate in the failing heart, and it is suggested that the derangement of the cardiac energy substrate metabolism plays a key role in the pathogenesis of heart failure.3 Manipulations that improve the oxidative capacity of the heart during disease might be beneficial for cardiac function and slow the progression of heart failure.MicroRNAs (miRNAs) are small, noncoding pieces of RNA that regulate gene expression by binding to recognition sequences that are usually located within the 3′-untranslated region (3′-UTR) of target genes. Binding of the miRNA to these sequences blocks the translational activity of these transcripts, leading to a reduction in protein formation.4 As is true for many aspects of heart disease, miRNAs have previously also been shown to be involved in the regulation of energy metabolism during heart failure.5A miRNA that has been linked to mitochondrial dysfunction of the heart is miR-181c. MiR-181c has been proposed to function in the mitochondrial compartment of cardiomyocytes by targeting mt-COX1 mRNA. Overexpression of miR-181c induced a loss of mt-COX1 expression, which led to an increase in mt-COX2 levels and subsequent remodeling of mitochondrial respiratory complex IV. The imbalance in components of complex IV induced an increase in mitochondrial respiration and the generation of reactive oxygen species, resulting in mitochondrial dysfunction. On the contrary, genetic deletion of miR-181c/d resulted in a smaller infarct size and maintenance of cardiac function in an ischemic heart failure model by improving the mitochondrial response to oxidative stress.6 These data indicate that mitochondrial perturbations induced by miR-181c could have important consequences in myocardial pathophysiology.Another example of miRNAs influencing cardiac energy metabolism is the miR-199a/miR-214 cluster. This miRNA cluster was found to be induced in heart failure in humans and mice. Both miR-199a and miR-214 coordinately regulate peroxisome proliferator-activated receptor δ, which is a critical regulator of cardiac energy metabolism that influences the metabolic shift toward glycolysis during heart failure. The importance of these miRNAs and the role of energy metabolism in heart disease were further underscored by the fact that therapeutic inhibition of both miRNAs was able to restore mitochondrial free fatty acid metabolism in a mouse model of heart failure resulting in an improved cardiac function.7In this issue of Circulation, the connection between mitochondrial energy production and cardiac remodeling has recently become even more apparent by a study from Heggermont et al.8 This study showed that miR-146a was found to be upregulated in both mouse models of pressure overload and in patients who have aortic stenosis. Either genetic deletion or therapeutic inhibition of miR-146a during pressure overload resulted in a blunted hypertrophic response and a better maintenance in cardiac function. In search for a mechanism in the absence of effects on inflammation, fibrosis, and angiogenesis, the researchers hypothesized that the observed effects might be related to an effect on cardiac metabolism. In focusing on factors involved in cardiomyocyte energy metabolism, they identified dihydrolipoamide succinyltransferase (DLST) as a potential target of miR-146a. DLST is a relatively understudied mitochondrial protein that functions as a tricarboxylic acid cycle transferase. Luciferase reporter assays using the 3′-UTR sequence of the murine DLST gene indicated that miR-146a is able to bind to the recognition sequences within the 3′-UTR of DLST to regulate its expression. The link between miR-146a and DLST was further confirmed in vivo by the increase in cardiac levels of DLST after anti-miR-146a treatment. Because of its involvement in energy metabolism, the authors went on to show that the metabolic changes occurring in cardiomyocytes after long-term angiotensin II exposure were normalized in the absence of miR-146a. In studying miR-146a knockout cells ex vivo, the authors showed that both glucose oxidation and fatty acid oxidation were preserved in miR-146a knockout cells when exposed to overload conditions. Thus, lowering miR-146a levels during pressure overload can give beneficial effects by derepressing DLST to create a favorable metabolic profile in cardiomyocytes that leads to diminished hypertrophy and an improvement in cardiac function.Because DLST was expected to play a major role in the observed cardioprotective effects, the authors next aimed to study the effect of cardiomyocyte-specific overexpression of DLST during angiotensin II–mediated pressure overload. In doing so, the authors were able to show that DLST overexpression in the heart significantly counteracted the pressure overload–induced hypertrophy. Although no data were presented on metabolic changes occurring in these hearts, the reduction in hypertrophy could suggest that an increase in DLST could have a beneficial effect on angiotensin II–induced cardiac remodeling because of its effect on energy metabolism.As mentioned previously, miRNAs exert their function through the regulation of coding transcripts. An intriguing aspect about miRNA research is that it can unveil the functional involvement of genes in processes they have not been previously linked to. In their article, Heggermont et al show that miR-146a can regulate DLST expression and thereby has a profound effect on cardiomyocyte energy metabolism, hypertrophy, and dysfunction during failure. Although DLST was previously shown to regulate mitochondrial ATP production in zebrafish hearts,9 so far it had not been related to cardiac remodeling in mammals, making DLST an important novel contributor to the metabolic changes that underlie cardiac remodeling during disease.With respect to target gene regulation, it should be noted that 1 single miRNA is capable of regulating several target genes in parallel, which do not necessarily overlap in function. In this regard, the upregulation of miR-146a was previously shown to be involved in doxorubicin-induced cardiotoxicity by the downregulation of Erb-B2 receptor tyrosine kinase 4 in cardiomyocytes.10 On the contrary, a cardioprotective function of miR-146a was described during ischemic injury, where an increase in miR-146a protected the heart against ischemic injury through the regulation of interleukin-1 receptor–associated kinase 1 and tumor necrosis factor receptor–associated factor 6, which blocked nuclear factor-κB activation. Also, when transgenically overexpressed in the endothelial cells of diabetic mice, miR-146a appeared to reduce the expression of inflammatory markers and prevented cardiac dysfunction via the regulation of interleukin-1 receptor–associated kinase 1 and tumor necrosis factor receptor–associated factor 6.11 It is currently unclear whether the influence of miR-146a on these targets contributes to the remodeling effects observed by Heggermont et al.8Like many miRNAs, miR-146a is expressed in multiple cardiac cell types, but appears to be enriched in endothelial cells. It is currently not well understood in which cell type miR-146a expression is upregulated during stress. It is interesting to note that several studies have shown that miR-146a can be transferred between cells via exosomal transfer. In a model of postpartum cardiomyopathy, exosomes released by endothelial cells were internalized by cardiomyocytes where they increased miR-146a levels and depressed contractile function. As such, therapeutic inhibition of miR-146a using an anti-miR approach attenuated a postpartum phenotype.12 In vitro cell-to-cell communication experiments shown by Heggermont et al8 also indicated that angiotensin II–induced stress does not appear to increase miR-146a expression in cardiomyocytes, but that it is rather the exosomal transfer of miR-146a from endothelial cells to cardiomyocytes that is responsible for the effects of miR-146a in the myocyte population. These studies suggest that the miR-146a levels in cardiomyocytes are, at least in part, coming from endothelial cells and point to the potential relevance of exosomal transfer of miRNAs. However, beneficial effects of exosomal delivery of miR-146a also have been reported for the heart. Exosomes derived from cardiac progenitor cells enriched for miR-146a were shown to mediate a cardioprotective effect during ischemic injury because of an antiapoptotic effect on cardiomyocytes.13,14 The divergent outcomes of miR-146a on cardiomyocyte function might be attributable to the difference in the underlying disease.15A common characteristic of miRNAs is their sequence conservation across species, which underscores their biological relevance. However, because the sequences of the 3′-UTRs are often less conserved, there might be species-dependent differences in target regulation. In the study by Heggermont et al, the authors define 3 potential recognition sequences for miR-146a in the murine 3′-UTR sequence of the DLST gene. However, because these binding site sequences are not identical in the human 3′-UTR sequence of DLST, it remains to be determined whether the proposed mechanism of miR-146a regulating cardiac DLST levels is conserved in the human heart.Despite some open-ended questions, the findings surrounding the influence of miR-146a and the function of DLST in cardiac metabolism are fascinating and deserve further pursuit. If these findings indeed translate into improving cardiac metabolism in the setting of human heart failure, locally increasing levels of DLST has the potential to become an attractive therapeutic approach to optimize cardiac energy metabolism during heart disease.Sources of FundingFunding was provided to Dr van Rooij by the Leducq Foundation (14CVD04) and the European Research Council under the European Union’s Seventh Framework Program (ERC Grant Agreement CoG 615708 MICARUS). Ms Demkes was funded by a grant from the Dalijn foundation.DisclosuresDr van Rooij is a scientific cofounder and SAB member of miRagen Therapeutics, Inc.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Eva van Rooij, PhD, Molecular Cardiology, Hubrecht Institute for Developmental Biology and Stem Cell Research, Royal Netherlands Academy of Arts and Sciences, 3584 CT Utrecht, The Netherlands. E-mail [email protected]