Adequate cardiac function results from proper synchronous activation of the cardiac chambers, leading to alternating systolic and diastolic phases. Electrical activation of the cardiac chambers is mainly controlled by cardiac conduction system. The main pacemaker of the heart is the slow-conducting sinoatrial node, which triggers and progressively spreads the electrical impulse towards the atrioventricular node through the atrial chambers. A time-delay in the atrioventricular node is followed by rapid activation of the His bundle and left and right bundle brunches to finalize on the peripheral Purkinje fiber network (1). Such a synchronous and coordinated activation of the atrial and ventricular chambers allows proper contraction of the cardiac chambers and thus blood propelling towards the entire organism.
Cardiac contractility is regulated by an exquisite interplay of thick and thin filaments that are regularly activated by calcium waves. Calcium regulation is mediated by a complex mechanism driving extracellular calcium into the myocyte by the L-type calcium channel (Cav1.2) and cyclically storing into the sarcoplasmic reticulum by the SR calcium pump (SERCA) and releasing through the ryanodine receptor (RyR). Additional control of the intracellular calcium levels is exerted at the plasma membrane by the sodium channels (Nav1.5) and the sodium calcium exchanger (Ncx) [for recent reviews see (2,3)].
Cardiac insults such as myocardial infarction frequently results in moderate to massive myocardial injury, upon which the heart responds firstly replacing the damage tissue with fibroblasts and/or myofibroblasts and secondly enhancing the myocardial mass by cardiomyocyte hypertrophy. Such initial adaptation might become maladaptive if the heart is unable to cope with the required physiological demands, leading to calcium handling abnormalities [for recent reviews see (4,5)]. Over the last decade investigation have aimed to minimize such functional disorders while limited information was obtained on the regulatory mechanisms driving these events.
It has been classically considered that the main regulatory mechanism of gene expression is the transcriptional regulation of protein coding RNAs. Over the last decade we have witnessed with large surprise that non-coding RNAs are at least 10-fold more abundant than protein-coding genes and that they display a wide range of functional regulatory capacities. In addition, they are capable of been transmitted from cell to cell by extracellular vesicles (6,7) and even between distinct organisms (8), the latter is still debated (9). At least two large families of non-coding RNAs have been described to date, i.e., long (lncRNAs; >200 nt in length) and small (sncRNAs; <200 nt in length) non-coding RNAs. Among them, microRNAs, a subclass of small non-coding RNAs, are the most well-studied. Within the cardiovascular context, tissue-restricted, circulating plasma and exosome contained microRNAs in different biofluids have been reported as biomarkers of distinct pathological conditions such as heart failure, myocardial infarction and congestive heart failure (10,11). Exosome-mediated delivery of microRNAs can provide both beneficial/protective (12,13) and damaging (14,15) effects to the heart. While ample information is available about the identification of candidate microRNAs as biomarkers, their reproducibility is still largely debated as well as their plausible cellular origin. In this context, an intriguing question is which are the cells that are delivering these extracellular vesicles to the circulation and which is their area of influence.
The study of Oh et al. (16) describes that upon cardiac injury fibroblast secreted exosomes containing miR-146a can influence SERCA function in the maladapted hypertrophic heart. microRNAs display tissue and developmental-specific expression in multiple developmental and diseases status. Several microRNAs have been reported to mediate cardiac electrophysiological modulation such as miR-219 and miR-192 to Scn5a (encoding Nav1.5) and miR-21 to Cacna1c (encoding Cav1.2) (17-19) while the regulation of Atp2a2 (encoding SERCA) by microRNAs remains largely unexplored. Interestingly, miR-146a has been widely described as biomarker of multiple pathological conditions, including cardiac pathology. Furthermore, miR-146a is frequently reported as an exosome-enriched microRNA in distinct cell types, including mesenchymal stem cells (20) and macrophages (21). miR-146a has also been reported as biomarker of cardiomyopathy (22) and heart failure (23), while its exogenous administration provides cardioprotective effects in distinct pathophysiological conditions (24,25), but to date modulation of molecular components regulating cardiac function have not been investigated. In this context, an important novelty reported by Oh et al. (16) is in fact putting into place the novel role of miR-146a modulating calcium handling. Such a modulatory mechanism is indirect, by regulation of post-translational SUMOylation. SUMOylation prevents degradation of the targeted proteins, providing therefore a larger half-life and thus their functional time window (26). SUMOylation has been previously reported targeting distinct components that modulate the electrophysiological properties of the adult heart, such as potassium channels, as well as SERCA in distinct homeotic and pathophysiological conditions such as myocardial infarction/reperfusion, heart failure as well as others settings of cardiac dysfunction (27-30). Therefore, intervening SUMOylation has been proposed as a plausible therapeutic intervention. In this context, Oh et al. (16) nicely demonstrate that modulating the functional capacities of a single microRNA, miR-146a, SUMOylation of SERCA can been altered resulting in enhanced capacities of calcium handling during cardiac physiopathological conditions.
Thus, the data presented in this paper provide seminal evidences in two fronts, on the one hand, the extracellular vesicle mediated cross-talk between fibroblasts and cardiomyocytes upon injury and on the other hand the microRNA-mediated post-translational modification of protein function via modulation of SUMOylation. Therefore, as pointed out by the authors, SUMO1 is identified as a new therapeutic target molecule for heart failure. These evidences open up the possibility of search for novel microRNAs that alone or in combination with miR-146a might further enhance the functional recovery of SERCA in cardiac maladaptive dysfunction and secondly, enlighten the possibility of modulating other cardiac contractile and/or electrophysiological disorders, by altering SUMOylation if the corresponding proteins are susceptible of suffering similar post-translational modifications, e.g., SUMOylation of potassium channels (30) underlying the onset of long-QT syndrome.
Conflicts of Interest: The authors have no conflicts of interest to declare.
- Franco D, Icardo JM. Molecular characterization of the ventricular conduction system in the developing mouse heart: topographical correlation in normal and congenitally malformed hearts. Cardiovasc Res 2001;49:417-29. [Crossref] [PubMed]
- Inesi G, Prasad AM, Pilankatta R. The Ca2+ ATPase of cardiac sarcoplasmic reticulum: Physiological role and relevance to diseases. Biochem Biophys Res Commun 2008;369:182-7. [Crossref] [PubMed]
- Dillmann WH. Calcium regulatory proteins and their alteration by transgenic approaches. Am J Cardiol 1999;83:89H-91H. [Crossref] [PubMed]
- Freichel M, Berlin M, Schürger A, et al. TRP Channels in the Heart. In: Emir TLR. editor. Neurobiology of TRP Channels. 2nd edition. Boca Raton (FL): CRC Press/Taylor & Francis, 2017. Chapter 9.
- Lipskaia L, Hulot JS, Lompré AM. Role of sarco/endoplasmic reticulum calcium content and calcium ATPase activity in the control of cell growth and proliferation. Pflugers Arch 2009;457:673-85. [Crossref] [PubMed]
- Murray LMA, Krasnodembskaya AD. Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells. Stem Cells 2019;37:14-25. [Crossref] [PubMed]
- Cruz L, Romero JAA, Iglesia RP, et al. Extracellular Vesicles: Decoding a New Language for Cellular Communication in Early Embryonic Development. Front Cell Dev Biol 2018;6:94. [Crossref] [PubMed]
- Zhang L, Hou D, Chen X, et al. Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Res 2012;22:107-26. [Crossref] [PubMed]
- Witwer KW, Hirschi KD. Transfer and functional consequences of dietary microRNAs in vertebrates: concepts in search of corroboration: negative results challenge the hypothesis that dietary xenomiRs cross the gut and regulate genes in ingesting vertebrates, but important questions persist. Bioessays 2014;36:394-406. [Crossref] [PubMed]
- Bei Y, Chen T, Banciu DD, et al. Circulating Exosomes in Cardiovascular Diseases. Adv Exp Med Biol 2017;998:255-69. [Crossref] [PubMed]
- Huang Q, Cai B. Exosomes as New Intercellular Mediators in Development and Therapeutics of Cardiomyocyte Hypertrophy. Adv Exp Med Biol 2017;998:91-100. [Crossref] [PubMed]
- Ailawadi S, Wang X, Gu H, et al. Pathologic function and therapeutic potential of exosomes in cardiovascular disease. Biochim Biophys Acta 2015;1852:1-11. [Crossref] [PubMed]
- Bollini S, Smits AM, Balbi C, et al. Triggering Endogenous Cardiac Repair and Regeneration via Extracellular Vesicle-Mediated Communication. Front Physiol 2018;9:1497. [Crossref] [PubMed]
- Nie X, Fan J, Li H, et al. miR-217 Promotes Cardiac Hypertrophy and Dysfunction by Targeting PTEN. Mol Ther Nucleic Acids 2018;12:254-66. [Crossref] [PubMed]
- Jiang X, Sucharov J, Stauffer BL, et al. Exosomes from pediatric dilated cardiomyopathy patients modulate a pathological response in cardiomyocytes. Am J Physiol Heart Circ Physiol 2017;312:H818-26. [Crossref] [PubMed]
- Oh JG, Watanabe S, Lee A, et al. miR-146a Suppresses SUMO1 Expression and Induces Cardiac Dysfunction in Maladaptive Hypertrophy. Circ Res 2018;123:673-85. [Crossref] [PubMed]
- Zhao Y, Huang Y, Li W, et al. Post-transcriptional regulation of cardiac sodium channel gene SCN5A expression and function by miR-192-5p. Biochim Biophys Acta 2015;1852:2024-34. [Crossref] [PubMed]
- Daimi H, Lozano-Velasco E, Haj Khelil A, et al. Regulation of SCN5A by microRNAs: miR-219 modulates SCN5A transcript expression and the effects of flecainide intoxication in mice. Heart Rhythm 2015;12:1333-42. [Crossref] [PubMed]
- Barana A, Matamoros M, Dolz-Gaitón P, et al. Chronic atrial fibrillation increases microRNA-21 in human atrial myocytes decreasing L-type calcium current. Circ Arrhythm Electrophysiol 2014;7:861-8. [Crossref] [PubMed]
- Pan J, Alimujiang M, Chen Q, et al. Exosomes derived from miR-146a-modified adipose-derived stem cells attenuate acute myocardial infarction-induced myocardial damage via downregulation of early growth response factor 1. J Cell Biochem 2018. [Epub ahead of print]. [Crossref] [PubMed]
- de Couto G, Gallet R, Cambier L, et al. Exosomal MicroRNA Transfer Into Macrophages Mediates Cellular Postconditioning. Circulation 2017;136:200-14. [Crossref] [PubMed]
- Halkein J, Tabruyn SP, Ricke-Hoch M, et al. MicroRNA-146a is a therapeutic target and biomarker for peripartum cardiomyopathy. J Clin Invest 2013;123:2143-54. [Crossref] [PubMed]
- Beg F, Wang R, Saeed Z, et al. Inflammation-associated microRNA changes in circulating exosomes of heart failure patients. BMC Res Notes 2017;10:751. [Crossref] [PubMed]
- Barile L, Lionetti V, Cervio E, et al. Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 2014;103:530-41. [Crossref] [PubMed]
- Ibrahim AG, Cheng K, Marbán E. Exosomes as critical agents of cardiac regeneration triggered by cell therapy. Stem Cell Reports 2014;2:606-19. [Crossref] [PubMed]
- Li XC, Zeng Y, Sun RR, et al. SUMOylation in cardiac disorders - a review. Eur Rev Med Pharmacol Sci 2017;21:1583-7. [PubMed]
- Qiu F, Dong C, Liu Y, et al. Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice. Toxicol Appl Pharmacol 2018;345:1-9. [Crossref] [PubMed]
- Du Y, Liu P, Xu T, et al. Luteolin Modulates SERCA2a Leading to Attenuation of Myocardial Ischemia/ Reperfusion Injury via Sumoylation at Lysine 585 in Mice. Cell Physiol Biochem 2018;45:883-98. [Crossref] [PubMed]
- Huang CY, Kuo CH, Pai PY, et al. Inhibition of HSF2 SUMOylation via MEL18 upregulates IGF-IIR and leads to hypertension-induced cardiac hypertrophy. Int J Cardiol 2018;257:283-90. [Crossref] [PubMed]
- Xiong D, Li T, Dai H, et al. SUMOylation determines the voltage required to activate cardiac I(Ks) channels. Proc Natl Acad Sci U S A 2017;114:E6686-94. [Crossref] [PubMed]
Cite this article as: Franco D, Dominguez JN. Novel regulatory pathways modulating cardiac contractile function: fibroblast to myocardial crosstalk via extracellular vesicles and non-coding RNAs. Non-coding RNA Investig 2019;3:3.