The Janus Face of miR-148a in Cardiac Remodeling and Heart Failure
Authors: Lisa Hobuß, Thomas Thum
Journal: Molecular Therapy (2019)

In ancient Roman religion, the god Janus represented beginnings and was most often depicted with two faces. In this issue of Molecular Therapy, Raso et al.1Raso A. Dirkx E. Philippen L.E. Fernandez-Celis A. De Majo F. Sampaio-Pinto V. Sansonetti M. Juni R. El Azzouzi H. Calore M. et al.Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure.Mol. Ther. 2018; 27 (this issue): 584-599Google Scholar report that microRNA-148a (miR-148a) is “Janus-like,” in that they show that it is regulated in an opposing fashion in human and mouse models of hypertrophic or dilated cardiomyopathy. They further provide evidence that transcriptional regulation of miR-148a represents a key event in the transition from concentric toward eccentric remodeling in pressure overload-induced cardiac hypertrophy. Heart failure is defined as the inability of the heart to supply the body with a sufficient amount of blood. However, with respect to the underlying causes and subsequent structural changes in cardiac geometry, the term “heart failure” encompasses heterogeneous clinical symptoms. A number of non-coding RNAs (ncRNAs), such as microRNAs or long non-coding RNAs (lncRNAs), have been reported to act as crucial regulators of cardiac remodeling and heart failure (reviewed in Bär et al.2Bär C. Chatterjee S. Thum T. Long noncoding RNAs in cardiovascular pathology, diagnosis, and therapy.Circulation. 2016; 134: 1484-1499Crossref PubMed Scopus (163) Google Scholar and Beermann et al.3Beermann J. Piccoli M.-T. Viereck J. Thum T. Non-coding RNAs in development and disease: background, mechanisms, and therapeutic approaches.Physiol. Rev. 2016; 96: 1297-1325Crossref PubMed Scopus (1116) Google Scholar). Most of the published studies used animal models of pressure overload to induce hypertrophic cardiac growth and reported either increased or decreased expression of ncRNA molecules. Therapeutic intervention to counteract endogenous regulation of several ncRNAs has been shown to reduce cardiac remodeling and improve cardiac function in treated animals.4van Rooij E. Sutherland L.B. Liu N. Williams A.H. McAnally J. Gerard R.D. Richardson J.A. Olson E.N. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure.Proc. Natl. Acad. Sci. USA. 2006; 103: 18255-18260Crossref PubMed Scopus (1296) Google Scholar, 5Carè A. Catalucci D. Felicetti F. Bonci D. Addario A. Gallo P. Bang M.L. Segnalini P. Gu Y. Dalton N.D. et al.MicroRNA-133 controls cardiac hypertrophy.Nat. Med. 2007; 13: 613-618Crossref PubMed Scopus (1503) Google Scholar, 6Ucar A. Gupta S.K. Fiedler J. Erikci E. Kardasinski M. Batkai S. Dangwal S. Kumarswamy R. Bang C. Holzmann A. et al.The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy.Nat. Commun. 2012; 3: 1078Crossref PubMed Scopus (447) Google Scholar, 7Karakikes I. Chaanine A.H. Kang S. Mukete B.N. Jeong D. Zhang S. Hajjar R.J. Lebeche D. Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling.J. Am. Heart Assoc. 2013; 2: e000078Crossref PubMed Scopus (208) Google Scholar, 8Viereck J. Kumarswamy R. Foinquinos A. Xiao K. Avramopoulos P. Kunz M. Dittrich M. Maetzig T. Zimmer K. Remke J. et al.Long noncoding RNA Chast promotes cardiac remodeling.Sci Transl Med. 2016; 8 (326ra22)Crossref PubMed Scopus (262) Google Scholar, 9Wang Z. Zhang X.J. Ji Y.X. Zhang P. Deng K.Q. Gong J. Ren S. Wang X. Chen I. Wang H. et al.The long noncoding RNA Chaer defines an epigenetic checkpoint in cardiac hypertrophy.Nat. Med. 2016; 22: 1131-1139Crossref PubMed Scopus (264) Google Scholar However, discrimination between ncRNA functions in different forms of hypertrophic cardiac growth has not received much attention. In 2013, a deep sequencing approach comparing healthy hearts and those from patients suffering from different forms of heart failure revealed that several hundred miRNAs were differentially regulated between healthy and failing hearts and, importantly, also between the different subtypes of heart failure patients with hypertrophic or dilated cardiomyopathy as underlying causes.10Leptidis S. El Azzouzi H. Lok S.I. de Weger R. Olieslagers S. Kisters N. Silva G.J. Heymans S. Cuppen E. Berezikov E. et al.A deep sequencing approach to uncover the miRNOME in the human heart.PLoS ONE. 2013; 8: e57800Crossref PubMed Scopus (68) Google Scholar In the current study, Raso et al.1Raso A. Dirkx E. Philippen L.E. Fernandez-Celis A. De Majo F. Sampaio-Pinto V. Sansonetti M. Juni R. El Azzouzi H. Calore M. et al.Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure.Mol. Ther. 2018; 27 (this issue): 584-599Google Scholar describe differences in the expression of their chosen target miR-148a showing contrasting regulation during different phases of pressure overload-induced cardiac remodeling. The findings provide evidence that a single microRNA can play different roles in distinct forms of heart failure and might even represent a crucial molecular switch in the establishment of either hypertrophic or dilated cardiomyopathy. Hypertrophic cardiac growth occurs as a compensatory response of the heart to changes in cardiac loading conditions in order to sustain normal cardiac function. In contrast to physiological hypertrophy during pregnancy or sustained exercise, chronic cardiovascular diseases such as hypertension, aortic stenosis, or others can lead to pathological cardiac hypertrophy and remodeling, which often sets the stage for the development of heart failure. With respect to the geometry of the heart, cardiac hypertrophy can be divided into concentric remodeling or hypertrophy (increase in ventricular wall thickness with or without changes in heart weight) and eccentric hypertrophy (increase in heart weight accompanied by left ventricular dilation) caused by pressure or volume overload, respectively.11Gaasch W.H. Zile M.R. Left ventricular structural remodeling in health and disease: with special emphasis on volume, mass, and geometry.J. Am. Coll. Cardiol. 2011; 58: 1733-1740Crossref PubMed Scopus (283) Google Scholar, 12Lang R.M. Badano L.P. Mor-Avi V. Afilalo J. Armstrong A. Ernande L. Flachskampf F.A. Foster E. Goldstein S.A. Kuznetsova T. et al.Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging.Eur. Heart J. Cardiovasc. Imaging. 2015; 16: 233-270Crossref PubMed Scopus (4274) Google Scholar A number of molecular signaling pathways have also been identified that coordinate hypertrophic cardiac growth (reviewed in Heineke and Molkentin13Heineke J. Molkentin J.D. Regulation of cardiac hypertrophy by intracellular signalling pathways.Nat. Rev. Mol. Cell Biol. 2006; 7: 589-600Crossref PubMed Scopus (1497) Google Scholar). In vitro experiments have shown that concentric and eccentric cardiomyocyte growth is driven by different growth factors, cytokines, or hormones interacting with different receptors. Molecules initiating signal transduction via G-protein coupled receptors, such as phenylephrine, are known to induce concentric hypertrophy, whereas members of the interleukin-6 (IL-6) superfamily, such as cardiotrophin-1 (CT-1) or leukemia-inhibitory factor (LIF), for example, have been shown to induce eccentric cardiomyocyte hypertrophy by interacting with the cytokine co-receptor glycoprotein 130 (gp130).14Wollert K.C. Taga T. Saito M. Narazaki M. Kishimoto T. Glembotski C.C. Vernallis A.B. Heath J.K. Pennica D. Wood W.I. Chien K.R. Cardiotrophin-1 activates a distinct form of cardiac muscle cell hypertrophy. Assembly of sarcomeric units in series VIA gp130/leukemia inhibitory factor receptor-dependent pathways.J. Biol. Chem. 1996; 271: 9535-9545Crossref PubMed Scopus (330) Google Scholar Following earlier microRNA profiling studies of cardiac biopsies from patients with hypertrophic and dilated cardiomyopathy, Raso et al.1Raso A. Dirkx E. Philippen L.E. Fernandez-Celis A. De Majo F. Sampaio-Pinto V. Sansonetti M. Juni R. El Azzouzi H. Calore M. et al.Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart Failure.Mol. Ther. 2018; 27 (this issue): 584-599Google Scholar revealed that miR-148a was differentialy regulated in concentric versus eccentric cardiac remodeling in humans. They further reported a dynamic expression profile of miR-148a in a mouse model of pressure overload-induced cardiac hypertrophy that revealed an induction of miR-148a during the phase of concentric cardiac remodeling. This induction of miR-148a was reversed when mouse hearts showed signs of eccentric cardiac remodeling accompanied by left ventricular chamber dilation and impaired systolic function. Concomitant with the peak in miR-148a, expression of gp130 and subsequent STAT3 phosphorylation were inhibited in animals subjected to transverse aortic constriction (TAC), whereas reduced expression of miR-148a at 6 and 8 weeks after TAC was associated with normalized gp130 expression. Using bioinformatics and in vitro approaches, the authors identified the gene encoding gp130 to be a direct target of miR-148a. In mice receiving TAC surgery, sustained overexpression of miR-148a using adeno-associated vectors (AAVs) did not prevent concentric hypertrophy, as shown by increased ventricular mass, but was sufficient to attenuate left ventricular dilation and cardiac fibrosis and also improved systolic function. Of note, miR-148a overexpression in sham animals failed to induce hypertrophic cardiac remodeling in the absence of additional stimuli. From their results, the authors concluded that repression of the gp130 receptor results in reduced sensitivity of cardiomyocytes toward CT-1 signaling and thereby prevents eccentric cardiac remodeling. The study provides strong evidence that differentially regulated microRNA expression levels can be observed in distinct forms of heart failure and, furthermore, that dynamic changes in miRNA expression could represent a key molecular switch in disease progression. Additionally, the miR-148a-gp130 regulatory circuit may thus represent a new putative therapeutic target to prevent ventricular dilation and the progression of heart failure in patients with pressure overload-induced cardiac hypertrophy. In clinical reality, eccentric and concentric remodeling features may both be present during different phases of the remodeling process. Thus, the exact timing and overall suitability of miR-148a modulation as a therapeutic strategy remains unclear. To phenotype eccentric versus concentric remodeling in patients at the cellular level would require biopsies, which complicates clinical translation of a therapeutic approach targeting miR-148a. Thus, these findings underline the importance of thorough discrimination between distinct forms of hypertrophic cardiac remodeling for further clinical application of microRNA therapeutics to prevent the development of heart failure. In order to get a deeper insight into the molecular basis of the transition from concentric toward eccentric remodeling in pressure overload-induced cardiac hypertrophy, it would be of interest to identify those molecular events that determine both the induction of miR-148a at the onset of concentric remodeling and the repression of miR-148a during the transition toward eccentric cardiac remodeling. In 2018, You et al.15You J. Wu J. Zhang Q. Ye Y. Wang S. Huang J. Liu H. Wang X. Zhang W. Bu L. et al.Differential cardiac hypertrophy and signaling pathways in pressure versus volume overload.Am. J. Physiol. Heart Circ. Physiol. 2018; 314: H552-H562PubMed Google Scholar compared morphological changes and signaling pathways in mouse models of pressure overload using TAC surgery and volume overload by aortic regurgitation and found clear differences in the activation of MAPK kinase family, β-arrestin-2, Akt, and Ca2+-related signaling pathways. Analysis of miR-148a expression in a model of volume overload might further reveal whether the cardiac miR-148a response differs between different forms of mechanical stress or is regulated by any of these pathways. In summary, this study is a first step on the way to exploring divergent miRNA function and regulation in different forms of cardiac hypertrophy and heart failure. T.T. filed and licensed patents in the field of noncoding RNAs. T.T. is a founder and holds shares of Cardior Pharmaceuticals, GmbH. Therapeutic Delivery of miR-148a Suppresses Ventricular Dilation in Heart FailureRaso et al.Molecular TherapyNovember 16, 2018In BriefRaso et al. show that miR-148a is elevated in concentric hypertrophy and decreased in dilated cardiomyopathy. Adeno-associated viral delivery of miR-148a protects the mouse heart from cardiac dilation. Mechanistically, miR-148a regulates the sensitivity of the heart to extracellular cytokines. Full-Text PDF Open Access