We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Functional role of miRNA in cardiac resynchronization therapy

    Celestino Sardu

    *Author for correspondence:

    E-mail Address: drsarducele@gmail.com

    Department of Medical, Surgical, Neurological, Metabolic & Geriatric Sciences, Second University of Naples, Piazza Miraglia, 2, 80138, Naples, Italy

    ,
    Raffaele Marfella

    Department of Medical, Surgical, Neurological, Metabolic & Geriatric Sciences, Second University of Naples, Piazza Miraglia, 2, 80138, Naples, Italy

    ,
    Gaetano Santulli

    Departments of Translational Medical Sciences & Advanced Biomedical Sciences, 'Federico II' University, Naples, Italy

    New York Presbyterian Hospital/Columbia University Medical Center, NY, USA

    &
    Giuseppe Paolisso

    Department of Medical, Surgical, Neurological, Metabolic & Geriatric Sciences, Second University of Naples, Piazza Miraglia, 2, 80138, Naples, Italy

    Published Online:https://doi.org/10.2217/pgs.14.76

    Heart failure (HF) disease progression is related to numerous adaptive processes including cardiac fibrosis, hypertrophy and apoptosis by activation of the ‘fetal’ gene program and downregulation of mRNA signatures, suggesting the importance of molecular mechanisms that suppress mRNA steady-state levels. miRNAs (miRs) are small, noncoding RNAs that bind mRNAs at their 3′-UTRs, leading to mRNA degradation or inhibition of protein translation. Several miRs are unregulated in response to cellular stress and can modify cellular functions such as proliferation, differentiation and programmed death; these miRs are also regulated in cardiac disease. Cardiac resynchronization therapy improves cardiac performance and myocardial mechanical efficiency. . In this updated critical appraisal we report on the main miRs that play a key role in response to cardiac resynchronization therapy (i.e., responder vs nonresponder HF patients), focusing on the miR-mediated modulation of cardiac angiogenesis, apoptosis, fibrosis and membrane ionic currents.

    Papers of special note have been highlighted as: • of interest

    References

    • 1 Cohn JN, Ferrari R, Sharpe N. Cardiac remodeling – concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. J. Am. Coll. Cardiol. 35(3), 569–582 (2000).
    • 2 Bouvagnet P, Leger J, Dechesne CA, Dureau G, Anoal M, Leger JJ. Local changes in myosin types in diseased human atrial myocardium: a quantitative immunofluorescence study. Circulation 72, 272–279 (1985).
    • 3 Mercadier JJ, de la Bastie D, Menasche P et al. Alpha-myosin heavy chain isoform and atrial size in patients with various types of mitral valve dysfunction: a quantitative study. J. Am. Coll. Cardiol. 9, 1024–1030 (1987).
    • 4 Tsuchimochi H, Sugi M, Kuro-o M et al. Isozymic changes in myosin of human atrial myocardium induced by overload. Immunohistochemical study using monoclonal antibodies. J. Clin. Invest. 74, 662–665 (1984).
    • 5 Hasenfuss G, Reinecke H, Studer R et al. Relation between myocardial function and expression of sarcoplasmic reticulum Ca(2+)- ATPase in failing and nonfailing human myocardium. Circ. Res. 75, 434–442 (1994).
    • 6 Kaab S, Barth AS, Margerie D et al. Global gene expression in human myocardium oligonucleotide microarray analysis of regional diversity and transcriptional regulation in heart failure. J. Mol. Med. 82, 308–316 (2004).
    • 7 Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
    • 8 Zernecke A, Bidzhekov K, Noels H et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009).
    • 9 Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell. Biol. 9, 654–659 (2007).
    • 10 Arroyo JD, Chevillet JR, Kroh EM et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
    • 11 Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).
    • 12 Mitchell PS, Parkin RK, Kroh EM et al. Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).
    • 13 Lawrie CH, Gal S, Dunlop HM et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br. J. Haematol. 141, 672–675 (2008).
    • 14 Chen X, Ba Y, Ma L et al. Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18, 997–1006 (2008).
    • 15 Tijsen AJ, Creemers EE, Moerland PD et al. MiR423–5p as a circulating biomarker for heart failure. Circ. Res. 106, 1035–1039 (2010).
    • 16 Marsit CJ, Eddy K, Kelsey KT. MicroRNA responses to cellular stress. Cancer Res. 66, 10843–10848 (2006).
    • 17 Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM. Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).
    • 18 Chen CZ, Li L, Lodish HF, Bartel DP. MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).
    • 19 He L, Thomson JM, Hemann MT et al. A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
    • 20 Santulli G, Totary-Jain H. Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics 14(12), 1517–1526 (2013).
    • 21 Volinia S, Calin GA, Liu CG. A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).
    • 22 Calin GA, Ferracin M, Cimmino A et al. A MicroRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N. Engl. J. Med. 353, 1793–1801 (2005).• Seminal study showing the importance of miRNAs in chronic lymphocytic leukemia.
    • 23 Bloomston M, Frankel WL, Petrocca F et al. MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297, 1901–1908 (2007).
    • 24 Schetter AJ, Leung SY, Sohn JJ et al. MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299, 425–436 (2008).
    • 25 van Rooij E, Sutherland LB, Liu N et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc. Natl Acad. Sci. USA 103, 18255–18260 (2006).  • Thorough paper illustrating the importance of miRNAs in left ventricular hypertrophy and heart failure.
    • 26 Sayed D, Hong C, Chen IY, Lypowy J, Abdellatif M. MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ. Res. 100, 416–424 (2007).
    • 27 Thum T, Galuppo P, Wolf C et al. MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258–267 (2007).
    • 28 Heerdt PM, Holmes JW, Cai B et al. Chronic unloading by left ventricular assist device reverses contractile dysfunction and alters gene expression in end-stage heart failure. Circulation 102, 2713–2719 (2000).
    • 29 Lowes BD, Gilbert EM, Abraham WT et al. Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N. Engl. J. Med. 346, 1357–1365 (2002).
    • 30 Sardu C, Marfella R, Santulli G . . . . Impact of diabetes mellitus on the clinical response to cardiac resynchronization therapy in elderly people. J. Cardiovasc Transl Res. 7, 362–368 (2014).
    • 31 Vanderheyden M, Mullens W, Delrue L et al. Myocardial gene expression in heart failure patients treated with cardiac resynchronization therapy responders versus nonresponders. J. Am. Coll. Cardiol. 51(2), 129–136 (2008).
    • 32 Meyer M, Schillinger W, Pieske B et al. Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92, 778–784 (1995).
    • 33 Kogler H, Schott P, Toischer K et al. Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression. Circulation 113, 2724–2732 (2006).
    • 34 White AJ, Arasaratnam D, Elliott DA, Kaye DM. Cellular reprogramming: a new avenue to cardiac regeneration? Circ. Heart Fail. 6(5), 1102–1107 (2013).
    • 35 Ramani R, Vela D, Segura A et al. A micro-ribonucleic acid signature associated with recovery from assist device support in 2 groups of patients with severe heart failure. J. Am. Coll. Cardiol. 58(22), 2270–2278 (2011).
    • 36 Marfella R, Di Filippo C, Potenza N et al. Circulating microRNA changes in heart failure patients treated with cardiac resynchronization therapy: responders vs. non-responders. Eur. J. Heart Fail. 15, 1277–1288 (2013).
    • 37 Boettger T, Beetz N, Kostin S, Schneider J, Krüger M, Hein L, Braun T. Acquisition of the contractile phenotype by murine arterial smooth muscle cells depends on the miR143/145 gene cluster. J. Clin. Invest. 119, 2634–2647 (2009).
    • 38 Cheng Y, Liu X, Yang J et al. MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ. Res. 105, 158–166 (2009).
    • 39 Cordes KR, Sheehy NT, White MP et al. miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 460, 705–710 (2009).
    • 40 Mann DL, Bristow MR. Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111, 2837–2849 (2005).
    • 41 Lee EJ, Gusev Y, Jiang J et al. Expression profiling identifies microRNA signature in pancreatic cancer. Int. J. Cancer 120(5), 1046–1054 (2007).
    • 42 Andreka P, Zang J, Dougherty C, Slepak TI, Webster KA, Bishopric NH. Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis. Circ. Res. 88(3), 305–312 (2001).
    • 43 Porrello ER. MicroRNAs in cardiac development and regeneration. Clin. Sci. (Lond.) 125(4), 151–166 (2013).
    • 44 Papoutsidakis N, Deftereos S, Kaoukis A et al. MicroRNAs and the heart: small things do matter. Curr. Top. Med. Chem. 13(2), 216–230 (2013).
    • 45 Santulli G, Iaccarino G, De Luca N, Trimarco B, Condorelli G. Atrial fibrillation and microRNAs. Front. Physiol. 5, 15 (2014).
    • 46 Liu L, Zhang G, Liang Z et al. MicroRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mitochondrial apoptotic pathwayApoptosis 19(1), 19–29 (2014).
    • 47 Romero DG, Plonczynski MW, Carvajal CA, Gomez-Sanchez EP, Gomez-Sanchez CE. Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells. Endocrinology 149(5), 2477–2483 (2008).
    • 48 Carmeliet P. Angiogenesis in health and disease. Nat. Med. 9, 653–660 (2003).
    • 49 Ji R, Cheng Y, Yue J et al. MicroRNA expression signature and antisense-mediated depletion reveal an essential role of MicroRNA in vascular neointimal lesion formation. Circ. Res. 100, 1579–1588 (2007).
    • 50 Romero DG, Plonczynski MW, Carvajal CA, Gomez-Sanchez EP, Gomez-Sanchez CE. Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells. Endocrinology 149, 2477–2483 (2008).
    • 51 Andreka P, Nadhazi Z, Muzes G et al. Possible therapeutic targets in cardiac myocyte apoptosis. Curr. Pharm. Des. 10(20), 2445–2461 (2004).
    • 52 Latronico MV, Catalucci D, Condorelli G. Emerging role of microRNAs in cardiovascular biology. Circ. Res. 101(12), 1225–1236 (2007).
    • 53 Santulli G, Ciccarelli M, Palumbo G et al. In vivo properties of the proangiogenic peptide QK. J. Transl. Med. 8(7), 41 (2009).
    • 54 Mann DL. MicroRNAs and the failing heart. N. Engl. J. Med. 356, 2644–2645 (2007).
    • 55 Manzano M, Shamulailatpam P, Raja AN, Gottwein E. Kaposi’s Sarcoma-associated herpesvirus encodes a mimic of cellular miR-23. J. Virol. 87(21), 11821–11830 (2013).
    • 56 Zhu SM, Si ML, Wu HL, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J. Biol. Chem. 282, 14328–14336 (2007).
    • 57 Bishopric NH, Andreka P, Slepak T, Webster KA. Molecular mechanisms of apoptosis in the cardiac myocyte. Curr. Opin. Pharmacol. 1(2), 141–150 (2001).
    • 58 Guerra S, Leri A, Wang X et al. Myocyte death in the failing human heart is gender dependent. Apoptosis is initiated by myocardial ischemia and executed during reperfusion. Circ. Res. 85(9), 856–866 (1999).
    • 59 Bridge G, Monteiro R, Henderson S et al. The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood 120(25), 5063–5072 (2012).
    • 60 van Rooij E, Sutherland LB, Liu N, Williams AH et al. A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc. Natl Acad. Sci. USA 103, 18255–18260 (2006).
    • 61 Corsten MF, Miranda R, Kasmieh R, Krichevsky AM, Weissleder R, Shah K. MicroRNA-21 knockdown disrupts glioma growth in vivo and displays synergistic cytotoxicity with neural precursor cell delivered S-TRAIL in human gliomas. Cancer Res. 67(19), 8994–9000 (2007).
    • 62 Chan JA, Krichevsky AM, Kosik KS. microRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65(14), 6029–6033 (2005).
    • 63 Karunakaran D, Rayner KJ. MicroRNAs in cardiovascular health: from order to disorder. Endocrinology 154(11), 4000–4009 (2013).
    • 64 Melkman-Zehavi T, Oren R, Kredo-Russo S et al. miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J. 30, 835–845 (2011).
    • 65 Lal A, Pan Y, Navarro F et al. miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. Nat. Struct. Mol. Biol. 16, 492–498 (2009).
    • 66 Chan MC, Hilyard AC, Wu C et al. Molecular basis for antagonism between PDGF and the TGFbeta family of signalling pathways by control of miR-24 expression. EMBO J. 29, 559–573 (2010).
    • 67 Dai Y, Khaidakov M, Wang X. MicroRNAs involved in the regulation of postischemic cardiac fibrosis. Hypertension 61(4), 751–756 (2013).
    • 68 Landgraf P, Rusu M, Sheridan R et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
    • 69 Fiedler J, Jazbutyte V, Kirchmaier BC et al. MicroRNA-24 regulates vascularity after myocardial infarction. Circulation 124, 720–730 (2011).
    • 70 Finn NA, Eapen D, Manocha P, Coronary heart disease alters intercellular communication by modifying microparticle-mediated microRNA transport. FEBS Lett. 587(21), 3456–3463 (2013).
    • 71 Zhao B, Zhu Y, Cui K, Gao J, Yu F, Chen L, Li S. Expression and significance of PTEN and miR-92 in hepatocellular carcinoma. Mol. Med. Rep. 7(5), 1413–1416 (2013).
    • 72 Romilda C, Marika P, Alessandro S et al. Oxidative DNA damage correlates with cell immortalization and miR-92 expression in hepatocellular carcinoma.BMC Cancer 15(12), 177 (2012).
    • 73 Sengul A, Santisuk R, Xing W, Kesavan C. Systemic administration of an antagomir designed to inhibit miR-92, a regulator of angiogenesis, failed to modulate skeletal anabolic response to mechanical loading. Physiol. Res. 62(2), 221–226 (2013).
    • 74 Santulli G, D’Ascia C. Atrial remodelling in echocardiographic super-responders to cardiac resynchronization therapy. Heart 98(6), 517 (2012).
    • 75 van Rooij E, Sutherland LB, Thatcher JE et al. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc. Natl Acad. Sci. USA 105, 13027–13032 (2008). • Important report describing the pivotal role of miRNA-29 in the pathophysiology of myocardial infarction.
    • 76 Olson EN. A decade of discoveries in cardiac biology. Nat. Med. 10, 467–474 (2004).
    • 77 Sorriento D, Santulli G, Fusco A, Anastasio A, Trimarco B, Iaccarino G. Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression. Hypertension 56, 696–704 (2010).
    • 78 Santulli G, Cipolletta E, Sorriento D et al. CaMK4 gene deletion induces hypertension. J. Am. Heart Assoc. 1, e001081 (2012).
    • 79 Allegra D, Bilan V, Garding A et al. Defective DROSHA processing contributes to downregulation of miR-15/-16 in chronic lymphocytic leukemia leukemia. Leukemia 28(1), 98–107 (2013).
    • 80 Small EM, Frost RJ, Olson EN. MicroRNAs add a new dimension to cardiovascular diseaseMicroRNAs add a new dimension to cardiovascular disease. Circulation 121, 1022–1032 (2010).
    • 81 Nass RD, Aiba T, Tomaselli GF, Akar FG. Mechanisms of disease: ion channel remodeling in the failing ventricle. Nat. Clin. Pract. Cardiovasc. Med. 5, 196–207 (2008).
    • 82 Zicha S, Fernandez-Velasco M, Lonardo G, L’Heureux N, Nattel S. Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc. Res. 66, 472–481 (2005).
    • 83 Dang X, Ma A, Yang L et al. MicroRNA-26a regulates tumorigenic properties of EZH2 in human lung carcinoma cells. Cancer Genet. 205(3), 113–123 (2012).
    • 84 Icli B, Wara AK, Moslehi J et al. MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling. Circ. Res. 113(11), 1231–1241 (2013).
    • 85 Luo X, Pan Z, Shan H. MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Invest. 123(5), 1939–1951 (2013).
    • 86 Lin CC, Lin CC, Lin JL et al. Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation. Chest 126(6), 1926–1932 (2004).
    • 87 Tavi P, Pikkarainen S, Ronkainen J et al. Pacing induced calcineurin activation controls cardiac Ca2+ signaling and gene expression. J. Physiol. 554(Pt 2), 309–320 (2004).
    • 88 Divarakan V, Mann DL. The emerging role of microRNAs in cardiac remodelling and heart failure. Circ. Res. 103, 1072–1083 (2008).
    • 89 Hullinger TG, Montgomery RL, Seto AG et al. Inhibition of miR-15 protects against cardiac ischemic injury. Circ. Res. 110(1), 71–81 (2012).
    • 90 Montgomery RL, Hullinger TG, Semus HM et al. Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124(14), 1537–1547 (2011).