Oxidative Stress-Responsive MicroRNAs in Heart Injury
Reactive oxygen species (ROS) are important molecules in the living organisms as a part of many signaling pathways. However, if overproduced, they also play a significant role in the development of cardiovascular diseases, such as arrhythmia, cardiomyopathy, ischemia/reperfusion injury (e. g. myocardial infarction, heart transplantation), and heart failure. As a result of oxidative stress action, apoptosis, hypertrophy, and fibrosis may occur. MicroRNAs (miRNAs) represent important endogenous nucleotides that regulate many biological processes including those involved in a heart damage by oxidative stress. Oxidative stress can alter the expression level of many miRNAs. These changes in miRNA expression occur mainly via modulation of Nrf2, sirtuins, NFAT/calcineurin, or NF-κB pathways. Up to now, several circulating miRNAs have been reported to be potential biomarkers of ROS-related cardiac diseases including myocardial infarction, hypertrophy, ischemia/reperfusion, and heart failure, such as miRNA-499, miRNA-199, miRNA-21, miRNA-144, miRNA-208a, miRNA-34a, etc. On the other hand, a lot of studies are aimed at using miRNAs for therapeutic purposes. This review points to the need for studying the role of redox-sensitive miRNAs to identify more effective biomarkers and develop better therapeutic targets for oxidative stress-related heart diseases.
Table of Contents [Hide]
Since 2001, miRNAs have been recognized as biomarkers and possible therapeutic targets for the diagnosis and treatment of diseases . One of the biggest advantages for using miRNAs as biomarkers is their stability under many different conditions. MiRNAs can be stored at room temperature, frozen, or thawed . Bioavailability of miRNA is another great advantage. MiRNAs can be isolated from various biological materials, like from peripheral blood, fresh and frozen tissues, or formalin-fixed, paraffin-wax-embedded samples, but also from saliva, epithelium of the skin, or hair . Difficulties in the use of therapeutically altering miRNAs lie in their non-specificity— single miRNA can target many genes and influence more than one gene expression, so they could affect also other pathways in the organisms . MiRNAs impose a relatively modest effect on their target, reflecting that individual mRNAs are targeted by multiple miRNAs, while the cellular proteome might be able to compensate the absence of a single miRNA .
Manipulation of RNA using miRNA mimics and antagomirs holds significant therapeutic potential for treating a variety of diseases. With recent technological advances, identification and validation of potential therapeutic miRNA targets are readily available . Treatment of diseases by modulation of selected miRNAs in the organisms is based on two approaches. First, miRNA mimics is an approach for gene silencing due to generating synthetized artificial double-stranded miRNA-like RNA fragments. These molecules are able to bind to target mRNA and suppressed genes . The second approach uses antagomirs, chemically designed oligonucleotides. These oligonucleotides specifically inhibit target miRNA by binding to them, which leads to reduction of RISC activation and to upregulation of genes . MiRNAs could be modulated also by miRNA sponges (target mimicry), masking, and erasers. MiRNA sponges contain a binding site for the miRNA family, leading to the blocking of the activity of miRNAs . Masking is based on the occupation of the binding site on target mRNA by oligonucleotides . Erasers are oligonucleotides complementary to specific miRNA, leading to inhibition of its function . However, delivery of anti-miRNAs and miRNAs in vivo may prove to be challenging .
Oxidative stress is one of the important contributing factors in cardiovascular disease genesis and development. Excessive ROS production has a significant impact on the pathogenesis of cardiovascular diseases related to atherosclerosis, cardiomyopathy, ischemia/reperfusion, and heart failure. Published literature highlights the increasing importance of studying the role of redox-sensitive miRNAs to identify more effective biomarkers and develop better therapeutic targets for oxidative-stress-related diseases. It is necessary to define the roles of individual miRNAs and their important targets, to determine their potential for possible diagnosis/treatment of cardiovascular disorders. Although a number of targets of oxidative-stress-responsive miRNAs have been identified, e.g., Nrf2, SIRT1, and NF-κB, future studies are still needed to determine further potential targets and their links to cardiovascular disease. MiRNA may be a promising novel tool and means in the clinical diagnosis, prognostic evaluation, and even therapeutic intervention of oxidative-stress-related CVD. The knowledge of the crosstalk between miRNAs, ROS, and cardiovascular diseases can contribute to new therapeutic approaches based on the suppression of ROS effects, with the potential to ameliorate or prevent the progression of cardiovascular diseases. However, several studies are still required to validate the present findings before the application of miRNA in clinical practice.
The article has been published on 10.3390/ijms21010358
- Christian Schulte; Tanja Zeller; microRNA-based diagnostics and therapy in cardiovascular disease—Summing up the facts. Cardiovascular Diagnosis and Therapy 2015, 5, 17-36, 10.3978/j.issn.2223-3652.2014.12.03.
- Syed Salman Ali; Chandra Kala; Mohd Abid; Nabeel Ahmad; Uma Shankar Sharma; Najam Ali Khan; Pathological microRNAs in acute cardiovascular diseases and microRNA therapeutics. Journal of Acute Disease 2016, 5, 9-15, 10.1016/j.joad.2015.08.001.
- Huseyin Altug Cakmak; Hasan Ali Barman; Ender Coskunpinar; Yasemin Musteri Oltulu; Baris Ikitimur; Gunay Can; Sevgi Ozcan; Vural Ali Vural; The Diagnostic Importance of MicroRNAs in Congestive Heart Failure. Journal of the American College of Cardiology 2013, 62, C17-C18, 10.1016/j.jacc.2013.08.060.
- Kevin A. Murach; John J. McCarthy; MicroRNAs, heart failure, and aging: potential interactions with skeletal muscle.. Heart Failure Reviews 2017, 22, 209-218, 10.1007/s10741-016-9572-5.
- Evan F. Lind; Pamela S. Ohashi; Mir-155, a central modulator of T-cell responses.. European Journal of Immunology 2014, 44, 11-15, 10.1002/eji.201343962.
- Paula A. Da Costa Martins; Kanita Salic; Monika M. Gladka; Anne-Sophie Armand; Stefanos Leptidis; Hamid El Azzouzi; Arne Hansen; Christina J. Coenen-De Roo; Marti F. Bierhuizen; Roel Van Der Nagel; et al. MicroRNA-199b targets the nuclear kinase Dyrk1a in an auto-amplification loop promoting calcineurin/NFAT signalling. Nature 2010, 12, 1220-1227, 10.1038/ncb2126.
- Joy N. Jones Buie; Andrew J. Goodwin; James A. Cook; Perry V. Halushka; Hongkuan Fan; The role of miRNAs in cardiovascular disease risk factors.. Atherosclerosis 2016, 254, 271-281, 10.1016/j.atherosclerosis.2016.09.067.
- Shlomit Gilad; Eti Meiri; Yariv Yogev; Sima Benjamin; Danit Lebanony; Noga Yerushalmi; Hila Benjamin; Michal Kushnir; Hila Cholakh; Nir Melamed; et al. Serum MicroRNAs Are Promising Novel Biomarkers. PLOS ONE 2008, 3, e3148, 10.1371/journal.pone.0003148.
- U Siebolts; H Varnholt; U Drebber; H-P Dienes; C Wickenhauser; M Odenthal; Tissues from routine pathology archives are suitable for microRNA analyses by quantitative PCR.. Journal of Clinical Pathology 2008, 62, 84-8, 10.1136/jcp.2008.058339.
- Andrea Gaarz; Svenja Debey-Pascher; Sabine Classen; Daniela Eggle; Birgit Gathof; Jing Chen; Jian-Bing Fan; Thorsten Voss; Joachim L. Schultze; Andrea Staratschek-Jox; et al. Bead Array–Based microRNA Expression Profiling of Peripheral Blood and the Impact of Different RNA Isolation Approaches. The Journal of Molecular Diagnostics 2010, 12, 335-344, 10.2353/jmoldx.2010.090116.
- Kevin C. Miranda; Tien Huynh; Yvonne Tay; Yen-Sin Ang; Wai-Leong Tam; Andrew M. Thomson; Bing Lim; Isidore Rigoutsos; A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes. Cell 2006, 126, 1203-1217, 10.1016/j.cell.2006.07.031.
- Eric N. Olson; MicroRNAs as therapeutic targets and biomarkers of cardiovascular disease.. Science Translational Medicine 2014, 6, 239ps3-239ps3, 10.1126/scitranslmed.3009008.
- Hao-Ran Wang; Meng Wu; Haibo Yu; Shunyou Long; Amy Stevens; Darren W. Engers; Henry Sackin; J. Scott Daniels; Eric S. Dawson; Corey R. Hopkins; et al. Selective Inhibition of the Kir2 Family of Inward Rectifier Potassium Channels by a Small Molecule Probe: The Discovery, SAR, and Pharmacological Characterization of ML133. ACS Chemical Biology 2011, 6, 845-856, 10.1021/cb200146a.