Abstract
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 . 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 . Local changes in myosin types in diseased human atrial myocardium: a quantitative immunofluorescence study. Circulation 72, 272–279 (1985).
- 3 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 Isozymic changes in myosin of human atrial myocardium induced by overload. Immunohistochemical study using monoclonal antibodies. J. Clin. Invest. 74, 662–665 (1984).
- 5 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 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 . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
- 8 Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci. Signal. 2, ra81 (2009).
- 9 . Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat. Cell. Biol. 9, 654–659 (2007).
- 10 Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc. Natl Acad. Sci. USA 108, 5003–5008 (2011).
- 11 . MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat. Cell Biol. 13, 423–433 (2011).
- 12 Circulating microRNAs as stable blood-based markers for cancer detection. Proc. Natl Acad. Sci. USA 105, 10513–10518 (2008).
- 13 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 Characterization of microRNAs in serum: a novel class of biomarkers for diagnosis of cancer and other diseases. Cell Res. 18, 997–1006 (2008).
- 15 MiR423–5p as a circulating biomarker for heart failure. Circ. Res. 106, 1035–1039 (2010).
- 16 . MicroRNA responses to cellular stress. Cancer Res. 66, 10843–10848 (2006).
- 17 . Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113, 25–36 (2003).
- 18 . MicroRNAs modulate hematopoietic lineage differentiation. Science 303, 83–86 (2004).
- 19 A microRNA polycistron as a potential human oncogene. Nature 435, 828–833 (2005).
- 20 . Tailoring mTOR-based therapy: molecular evidence and clinical challenges. Pharmacogenomics 14(12), 1517–1526 (2013).
- 21 . A microRNA expression signature of human solid tumors defines cancer gene targets. Proc. Natl Acad. Sci. USA 103, 2257–2261 (2006).
- 22 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 MicroRNA expression patterns to differentiate pancreatic adenocarcinoma from normal pancreas and chronic pancreatitis. JAMA 297, 1901–1908 (2007).
- 24 MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma. JAMA 299, 425–436 (2008).
- 25 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 . MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ. Res. 100, 416–424 (2007).
- 27 MicroRNAs in the human heart: a clue to fetal gene reprogramming in heart failure. Circulation 116, 258–267 (2007).
- 28 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 Myocardial gene expression in dilated cardiomyopathy treated with beta-blocking agents. N. Engl. J. Med. 346, 1357–1365 (2002).
- 30 . . . . Impact of diabetes mellitus on the clinical response to cardiac resynchronization therapy in elderly people. J. Cardiovasc Transl Res. 7, 362–368 (2014).
- 31 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 Alterations of sarcoplasmic reticulum proteins in failing human dilated cardiomyopathy. Circulation 92, 778–784 (1995).
- 33 Relevance of brain natriuretic peptide in preload-dependent regulation of cardiac sarcoplasmic reticulum Ca2+ ATPase expression. Circulation 113, 2724–2732 (2006).
- 34 . Cellular reprogramming: a new avenue to cardiac regeneration? Circ. Heart Fail. 6(5), 1102–1107 (2013).
- 35 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 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 . 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 MicroRNA-145, a novel smooth muscle cell phenotypic marker and modulator, controls vascular neointimal lesion formation. Circ. Res. 105, 158–166 (2009).
- 39 miR-145 and miR-143 regulate smooth muscle cell fate and plasticity. Nature. 460, 705–710 (2009).
- 40 . Mechanisms and models in heart failure: the biomechanical model and beyond. Circulation 111, 2837–2849 (2005).
- 41 Expression profiling identifies microRNA signature in pancreatic cancer. Int. J. Cancer 120(5), 1046–1054 (2007).
- 42 . Cytoprotection by Jun kinase during nitric oxide-induced cardiac myocyte apoptosis. Circ. Res. 88(3), 305–312 (2001).
- 43 . MicroRNAs in cardiac development and regeneration. Clin. Sci. (Lond.) 125(4), 151–166 (2013).
- 44 MicroRNAs and the heart: small things do matter. Curr. Top. Med. Chem. 13(2), 216–230 (2013).
- 45 . Atrial fibrillation and microRNAs. Front. Physiol. 5, 15 (2014).
- 46 MicroRNA-15b enhances hypoxia/reoxygenation-induced apoptosis of cardiomyocytes via a mitochondrial apoptotic pathway. Apoptosis 19(1), 19–29 (2014).
- 47 . Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells. Endocrinology 149(5), 2477–2483 (2008).
- 48 . Angiogenesis in health and disease. Nat. Med. 9, 653–660 (2003).
- 49 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 . Microribonucleic acid-21 increases aldosterone secretion and proliferation in H295R human adrenocortical cells. Endocrinology 149, 2477–2483 (2008).
- 51 Possible therapeutic targets in cardiac myocyte apoptosis. Curr. Pharm. Des. 10(20), 2445–2461 (2004).
- 52 . Emerging role of microRNAs in cardiovascular biology. Circ. Res. 101(12), 1225–1236 (2007).
- 53 In vivo properties of the proangiogenic peptide QK. J. Transl. Med. 8(7), 41 (2009).
- 54 . MicroRNAs and the failing heart. N. Engl. J. Med. 356, 2644–2645 (2007).
- 55 . Kaposi’s Sarcoma-associated herpesvirus encodes a mimic of cellular miR-23. J. Virol. 87(21), 11821–11830 (2013).
- 56 . MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J. Biol. Chem. 282, 14328–14336 (2007).
- 57 . Molecular mechanisms of apoptosis in the cardiac myocyte. Curr. Opin. Pharmacol. 1(2), 141–150 (2001).
- 58 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 The microRNA-30 family targets DLL4 to modulate endothelial cell behavior during angiogenesis. Blood 120(25), 5063–5072 (2012).
- 60 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 . 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 . microRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65(14), 6029–6033 (2005).
- 63 . MicroRNAs in cardiovascular health: from order to disorder. Endocrinology 154(11), 4000–4009 (2013).
- 64 miRNAs control insulin content in pancreatic beta-cells via downregulation of transcriptional repressors. EMBO J. 30, 835–845 (2011).
- 65 miR-24-mediated downregulation of H2AX suppresses DNA repair in terminally differentiated blood cells. Nat. Struct. Mol. Biol. 16, 492–498 (2009).
- 66 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 . MicroRNAs involved in the regulation of postischemic cardiac fibrosis. Hypertension 61(4), 751–756 (2013).
- 68 A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).
- 69 MicroRNA-24 regulates vascularity after myocardial infarction. Circulation 124, 720–730 (2011).
- 70 , Coronary heart disease alters intercellular communication by modifying microparticle-mediated microRNA transport. FEBS Lett. 587(21), 3456–3463 (2013).
- 71 . Expression and significance of PTEN and miR-92 in hepatocellular carcinoma. Mol. Med. Rep. 7(5), 1413–1416 (2013).
- 72 Oxidative DNA damage correlates with cell immortalization and miR-92 expression in hepatocellular carcinoma.BMC Cancer 15(12), 177 (2012).
- 73 . 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 . Atrial remodelling in echocardiographic super-responders to cardiac resynchronization therapy. Heart 98(6), 517 (2012).
- 75 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 A decade of discoveries in cardiac biology. Nat. Med. 10, 467–474 (2004).
- 77 . Intracardiac injection of AdGRK5-NT reduces left ventricular hypertrophy by inhibiting NF-kappaB-dependent hypertrophic gene expression. Hypertension 56, 696–704 (2010).
- 78 CaMK4 gene deletion induces hypertension. J. Am. Heart Assoc. 1, e001081 (2012).
- 79 Defective DROSHA processing contributes to downregulation of miR-15/-16 in chronic lymphocytic leukemia leukemia. Leukemia 28(1), 98–107 (2013).
- 80 MicroRNAs add a new dimension to cardiovascular diseaseMicroRNAs add a new dimension to cardiovascular disease. Circulation 121, 1022–1032 (2010).
- 81 . Mechanisms of disease: ion channel remodeling in the failing ventricle. Nat. Clin. Pract. Cardiovasc. Med. 5, 196–207 (2008).
- 82 . Sinus node dysfunction and hyperpolarization-activated (HCN) channel subunit remodeling in a canine heart failure model. Cardiovasc. Res. 66, 472–481 (2005).
- 83 MicroRNA-26a regulates tumorigenic properties of EZH2 in human lung carcinoma cells. Cancer Genet. 205(3), 113–123 (2012).
- 84 MicroRNA-26a regulates pathological and physiological angiogenesis by targeting BMP/SMAD1 signaling. Circ. Res. 113(11), 1231–1241 (2013).
- 85 . MicroRNA-26 governs profibrillatory inward-rectifier potassium current changes in atrial fibrillation. J. Clin. Invest. 123(5), 1939–1951 (2013).
- 86 Activation of the calcineurin-nuclear factor of activated T-cell signal transduction pathway in atrial fibrillation. Chest 126(6), 1926–1932 (2004).
- 87 Pacing induced calcineurin activation controls cardiac Ca2+ signaling and gene expression. J. Physiol. 554(Pt 2), 309–320 (2004).
- 88 . The emerging role of microRNAs in cardiac remodelling and heart failure. Circ. Res. 103, 1072–1083 (2008).
- 89 Inhibition of miR-15 protects against cardiac ischemic injury. Circ. Res. 110(1), 71–81 (2012).
- 90 Therapeutic inhibition of miR-208a improves cardiac function and survival during heart failure. Circulation 124(14), 1537–1547 (2011).