- Email: [email protected]
Role of circulating miRNAs in the pathophysiology of CVD: As a potential biomarker
Accepted Manuscript The role of circulating miRNAs in the pathophysiology of CVD: As a potential biomarker
Reena Kumari, Sandeep Kumar, Ravikant PII: DOI: Reference:
S2452-0144(18)30124-9 doi:10.1016/j.genrep.2018.10.003 GENREP 327
To appear in:
Gene Reports
Received date: Revised date: Accepted date:
30 May 2018 21 September 2018 5 October 2018
Please cite this article as: Reena Kumari, Sandeep Kumar, Ravikant , The role of circulating miRNAs in the pathophysiology of CVD: As a potential biomarker. Genrep (2018), doi:10.1016/j.genrep.2018.10.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review Article The role of Circulating miRNAs in the pathophysiology of CVD: As a potential biomarker Reena Kumari*1,2 , Sandeep Kumar*3 and Ravikant4
IP
T
1. Department of Zoology University of Lucknow, Lucknow
CR
2. Department of Biochemistry, King George’s Medical University, Lucknow-226003
M
AN
4. Department of General Surgery, AIIMS, Rishikesh
US
3. Department of Biochemistry, AIIMS, Rishikesh
AC
CE
PT
Dr. Reena Kumari Research Associate Department of Biochemistry KGMU, Lucknow [email protected]
ED
*Address to correspondence:
Conflict of Interest: - None
Dr. Sandeep Kumar Demonstrator Department of Biochemistry AIIMS, Rishikesh
[email protected]
ACCEPTED MANUSCRIPT Abstracts- Cardio Vascular Disease (CVD) has raised morbidity and mortality rate in near future and also remains a major financial burden in most developed countries around the world wide. According to World Health Organization (WHO) an estimated 17.5 million people died each year by CVD and more than 75 percent of CVD deaths are due to heart attacks and
T
strokes. Approximately half of these deaths are mostly occur in adults and middle aged person.
IP
In past few years specific Micro RNAs (miRNA) expression patterns have been regulates the
CR
various medical conditions and which are associated in the development of CVD. These miRNAs are small, non-coding, RNA molecules approximately 22 nucleotides in length which
US
regulate a large fraction of genome by binding to complementary messenger RNA sequences,
AN
resulting in translational repression and gene silencing and are also found in all eukaryotic cells. To date approximately 2200 miRNA genes have been reported to exist in the mammalian
M
genome from which over 1000 belong to the human genome. miRNAs have been involved in
ED
inter cellular communication and have been shown to circulate in the blood stream in cell free forms. Individual miRNAs have been shown to regulate the expression of multiple genes.
PT
Conversely, the expression of individual genes can be regulated by multiple miRNAs.
CE
Therefore, In the present study we have aimed to investigate the role of miRNAs in the pathophysiology of CVD. Conclusively we have found that these miRNAs are play as potential
AC
biomarkers in early diagnosis and therapeutic targets for CVD.
Keywords: miRNA, CVD, Pathophysiology, Progression
ACCEPTED MANUSCRIPT 1.
Introduction-
Cardiovascular diseases, mainly coronary artery diseases (CAD) which are posing a high socioeconomic burden on the health worldwide [1], of all 60 million cases of deaths from all causes worldwide in 2005, an estimated 18 million were due to cardiovascular diseases, three
T
times more than caused by infectious diseases including HIV/AIDS, tuberculosis, and malaria
IP
combined [2]. MicroRNAs are important post-transcriptional regulators of genes. In humans,
CR
about one-third of the genes are regulated by microRNAs, which suggests an important
US
regulatory role of microRNAs in gene expression and hence phenotype determination [3]. It is estimated that the human genome encodes approximately 1000 miRNAs. Among them, more
AN
than 100 have been identified in sera from healthy subjects and are designated circulating miRNAs. Unlike intracellular mRNAs, circulating miRNAs show remarkable stability and
M
resistance to degradation by endogenous RNase activity. The majority of the circulating
ED
miRNAs are derived from blood cells with others from various tissues such as heart, lung, liver
PT
and kidney. The stability of circulating miRNAs has stimulated interest in their use as biomarkers for the diagnosis and prognosis of various diseases including CVD [4]. Most
CE
miRNAs differ in temporal or spatial expression patterns in the body, such as miR-1/miR133, which are specifically expressed in muscles [5]. These tiny molecules show tremendous gene
AC
regulatory potential and play a key role in pathophysiology of almost all organs, including the cardiovascular system [6] and Changes in miRNA expression profiles are noted during cardiogenesis as well as progression of heart diseases, indicating miRNA deregulation to be mechanistically involved in cardiovascular pathologies [6,7,8] miRNAs are a group of noncoding regulatory RNAs and participate in a surprisingly diverse collection of regulatory events. which are a family of about 22 nucleotides that control gene expression at the post-
ACCEPTED MANUSCRIPT transcriptional level [9]. It is well established that miRNAs play critical roles in the physiological and pathological processes in cardiovascular system, such as endothelial dysfunction, inflammation, apoptosis, angiogenesis, atherosclerosis [10-13] and also play crucial role in cell differentiation, cell growth, mobility and apoptosis.
IP
T
2. The biogenesis of miRNAs
MicroRNAs (miRNAs) are endogenous small non-coding RNAs with 21-25 nucleotides in
CR
length. By pairing with the 3’ UTR of target mRNAs, miRNAs can regulate protein-coding
US
genes at the posttranscriptional level via degradation of mRNAs or repression of protein translation [14]. The first micro RNA was discovered in nematode Caenorhabditis elegans by
AN
the Ambros group at Harvard University in 1993 [15]. The biogenesis of miRNA are governed
M
by several regulatory check points, generally the miRNAs are transcribed by RNA polymerase II and infrequently by RNA polymerase III [16], miRNAs are derive from noncoding transcripts
ED
which are also co-expressed with the host gene transcript or located in intergenic regions of the
PT
genome. The primary miRNA transcripts are transcribed as the precursor molecules known as pri-miRNAs which are contain a canonical hairpin structure, a 50 cap and a 30 poly-A tail [17],
CE
derived either from annotate transcripts or from intergenic regions within the genome and can
AC
predetermine a single or multiple miRNAs [18,19]. Pri-miRNAs fold into hairpin structures containing improperly base-paired stems and which are transcripts in the nucleus by the Drosha complex and processed into 60 to 100 nucleotides hairpins known as pre-miRNAs [20-22] after that it is exported from the nucleus to the cytoplasm by exportin 5 [23], and usually cleaved by the endonuclease Dicer and give up imperfect miRNA-miRNA duplexes [24]. These miRNAmiRNA duplexes are converted into a mature miRNA. However, most often the miRNA strand is degraded and incorporated into RNA-induced silencing complex (RISC) and these complex
ACCEPTED MANUSCRIPT are recognizing by particular targets and promote the post-transcriptional gene silencing [25] which carries out the regulatory function of miRNAs by the binding of the target mRNA and either promoting its degradation or inhibiting its translation. Moreover, an alternative biogenesis pathway was currently discovered in which miR-451 enters RISC by direct loading
T
of the pre-miR into RISC after Drosha processing, by skipping further processing by Dicer [26]
AC
CE
PT
ED
M
AN
US
CR
IP
(Figure 1).
Figure1: The schematic representation of biogenesis of miRNA
ACCEPTED MANUSCRIPT 3. miRNA in CVD progression and development Cardio vascular Disease is a clinical diagnosis when the heart fails to provide sufficient circulatory force to meet the body’s metabolic requirements. It is one of the major causes of mortality in the US, responsible for ~30% of patient deaths annually and also in other
T
developing countries like India. Heart failure is the final manifestation of CVD and cardiac
IP
injury, as well as less common but important etiologies including cardiomyopathies, valvular
CR
heart disease, prolonged arrhythmias, myocarditis, infections and exposure to cardiotoxic drugs circulating miRNAs have been identified as potential biomarkers of CVDs [4]. miRNA are play
US
key role in the pathophysiology of CVD progression and development which are regulate gene
AN
expression of mature mRNA at the post transcriptional level during transcript degradation or translational suppression by binding to the 3’ UTR of the target mRNA so that we can say each
M
miRNA have hundreds of target mRNAs for its permissive binding state of mRNA, signifying
ED
that an each mRNA is regulated by several miRNAs and several miRNA regulates more than one mRNAs and which are constitute a new class of distinctive molecular regulators involved
PT
in the pathophysiology of miRNAs comprise a new class of unique molecular regulators
CE
involved in the pathophysiology of CVD. miRNAs play significant roles in CVD development and also their expression profile changes according to different pathological conditions.
AC
Previous studies have suggested that the evaluated miRNAs have been identified in cardiac tissue at all stages of development and it is now acknowledged that miRNAs are involved in nearly all forms of CVDs. We have discussed the role of miRNA in many forms of CVDs. (a). Circulating miRNAs and AtherosclerosisAtherosclerosis, are a condition where the arteries become hardened and narrowed due to an excessive deposite of plaque inside the arteries. Plaque is made of cholesterol, cellular waste
ACCEPTED MANUSCRIPT products, calcium, fatty substances and fibrin (a clotting material in the blood). Previous studies have investigated the role of miRNAs in development of atherosclerosis. Many miRNAs are directly or indirectly regulate endothelial dysfunction (ECs), lipid dysregulation, infiltration of inflammatory cells and vascular smooth muscle cell (VSMC) differentiation through their
T
specific miRNA-155 play a key role in to the infiltration of inflammatory cells and their
IP
permeability increased by ECs [27, 28]. miRNAs are also a key regulatory molecules in
CR
platelets, immune cells, VSMC, and ECs which are responsible to the initiation and progression of atherosclerosis and ECs [29]. It has been reveals a range of miRNAs like as (miR-10a, miR-
US
19a, miR-23b, miR-17-92, miR-21, miR-24, miR-92a, miR-101, miR-126, miR-145, miR-155,
AN
miR205, miR-663, and miR-712 are highly significantly expressed in atherosclerosis, angiogenesis, and arterial remodeling [30, 31]. Although, MMPs associated to atherosclerotic
M
plaque progression, destabilization, and Oxidized LDL, plays a crucial role in atherosclerosis,
PT
migration of VSMC [32].
ED
through increases miRNA-29b expression in MMP-2 and MMP-9 which are increases the
CE
(b). Circulating miRNAs and arrhythmiasAn arrhythmia describes an irregular heartbeat it is also called Atrial fibrillation. There are two
AC
basic kinds of arrhythmias one is Bradycardia, when the heart beat too slow- less than 60 beats per minute and second is called tachycardia when the heart may beat too fast more than 100 beats per minute. The circulating level of miR-328 are highly elevated 3.5 fold in atrial fibrillation patients in comparison to without AF person and the level of miR-223 and miR-664 were also elevated in AF but most interestingly, miR-1 was unaffected [33].
ACCEPTED MANUSCRIPT (c). Circulating miRNAs and Coronary artery disease Coronary artery disease also called coronary heart diseases is a common term for the buildup of plaque in the heart’s arteries that could lead to heart attack. The various number of miRNAs have been linked to a diagnosis of coronary artery disease. Some studies have been associated
IP
T
with potential role of miRNA in CAD patients. The Circulating levels of miR-1, miR-122,
CR
miR-133a, miR-133b miR-208a, miR-337-5p, miR-433, and miR-485-3p were significantly upregulated, whereas miR-17, miR-92a, miR-126, miR-145, miR-155, and miR-199a levels were
US
markedly down-regulated in CAD [34, 35]. The Previous studies showed that the circulating level of miR-424 and miR-149 in plasma were significantly down-regulated, while the level of
AN
miR-765 in plasma were up-regulated in stable and unstable CAD patients compared with
M
healthy control. The values of AUC (area under the curve) for miR-149, miR-424 and miR-765 were significantly increases in stable CAD patients (0.938, 0.919 and 0.968, respectively) and
ED
in unstable CAD patients (0.951, 0.960 and 0.977, respectively) compared with healthy control.
PT
previous results showed that the plasma level of miR-149 and miR-424 were significantly down-regulated, whereas plasma level of miR-765 were up-regulated in stable and unstable
CE
CAD patients compared with healthy control [36].
AC
(d). Circulating miRNAs and Acute coronary syndromes Acute coronary syndrome denotes a range of disorders, including a heart attack (myocardial infarction) and unstable angina, which are caused by the same underlying problems. According to the Cardiologists, the ACS divided into three distinct clinical patterns in which two of them represent different forms of MI like as ST-Elevation myocardial infarction (STEMI) & NonST-Elevation myocardial infarction (NSTEMI) and another one represents a severe form of
ACCEPTED MANUSCRIPT angina, called "unstable angina these all three are caused by acute blood clots in the coronary arteries. The circulating miRNAs are a new biomarker for ACS and play an important role in diagnosis, prediction, prognosis and reaction in ACS patients the outline of circulating miRNAs as the diagnostic biomarkers for ACS [37]. Previous study shows that the levels of six miRNAs
T
like as miR-208a, miR-499, miR-499-5p miR-1, miR-133a, miR-133b, in 224 AMI patients out
IP
of which the level of miR-208b, miR-320a and miR-499-5p were found significantly higher in
CR
Acute myocardial infarction patients compared to healthy controls [38]. Several miRNAs are
US
responsible for the diagnosis of different forms of ACS which are follows as- (Figure-2) (i). Unstable Angina (UA)- Circulating level of miR-1, miR-122, miR-126, miR-133a/b, miR-
AN
199a, miR-485-3p were all upregulated in stable form and unstable angina, even as the
M
circulating level of miR-145 was significantly elevated only in unstable angina [36]. (ii). Non-ST-Elevation Myocardial Infarction (NSTEMI)- In a very recent study, the level
ED
of miRNA-499-5p was elevated in plasma of NSTEMI patients and to be reported that The
PT
diagnostic accuracy of miRNA-499-5p was even higher than conventional and high-sensitivity cTnT (hs-cTnT) in differentiating NSTEMI form of ACS [39].
CE
(iii). ST-Elevation Myocardial Infarction (STEMI)- miR-133a level are elevated in STEMI
AC
forms and shows up-regulated and also observed significant correlations with ACS [40], miR30c and miR-145 were also positively up-regulated in STEMI Forms [41, 42].
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
ED
Figure 2: Overview of circulating microRNAs in acute coronary syndrome. Unstable angina; NSTEMI: Non-ST- segment elevated myocardial infarction; STEMI: ST segment elevated myocardial infarction.
PT
4. miRNA modulation as a therapeutic approach challenges
CE
According to the previous studies, the miRNA plays a key role in gene regulation and provide promising therapeutic targets but currently The biggest challenge here lies in the capability to
AC
predict the accurate results due to It is accepted that micro RNAs are not specific for their regulation of a single gene. actually, they can modulate hundreds of target genes and causes effects of miRNA modulation in the human body [43]. circulating micro RNAs can play a diagnostic or prognostic purposes in cardiovascular disease and which are described an approach in which micro RNA function was blocked by scavenging away from the miRNA and they are called “miRNA sponges” and these miRNA sponges Possessing multiple binding sites,
ACCEPTED MANUSCRIPT through the bind up to a programmed RNA-induced silencing complex and reducing its availability and effective function of entire micro RNA families [44]. 5. ConclusionConclusively, we have found that circulating miRNAs have emerged as novel promising
T
biomarkers for cardio vascular diseases including its role in diagnosis, prediction, prognosis and
IP
reaction to therapy. So present study reveals that these miRNAs play a key role in development
CR
of cardiovascular disease and may be used as a potential biomarker for early detection of cardio vascular disease like myocardial infarction. Further study will be needed to explore the role of
AN
pathophysiology of cardiovascular diseases.
US
these miRNAs in the mechanistic view on different metabolic pathway which is involved in the
6. Conflicts of interest- The authors declare that there is no conflict of interests regarding the
ED
M
publication of this paper.
PT
References:-
Nishiguchi, Toshio Imanishi, and Takashi Akasaka: MicroRNAs and Cardiovascular Diseases BioMed Research InternationalVolume 2015; 14 Health Organization,(2013). CardiovascularDiseases. http://www.who.int/cardiovascular_ diseases/en/ [accessedMarch27, 2013].
3.
Availableat:
AC
2. World
CE
1. Tsuyoshi
Paneru, B.,D., Al-Tobasei, R., Kenney, B., Leeds, T.D., Salem, M,. RNA-Seq reveals icroRNA expression signature and genetic polymorphism associated with growth and muscle quality traits in rainbow trout. Sci Rep. 2017 Aug 22;7(1):9078.
4. Zhou, S.S., Jin, J.P., Wang, J.Q., Zhang, Z.G., Freedman, J.H., Zheng, Y., Cai L. miRNAS
in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges. Acta Pharmacol Sin. 2018 Jul;39(7):1073-1084. Mattick, J.S., Makunin I.V., Small regulatory RNAs in mammals. Hum Mol Genet 2005;14Spec No 1:R121–R132. 5.
ACCEPTED MANUSCRIPT Ikeda, S., Kong, S.W., Lu, J., Bisping, E., Zhang, H., Allen, P. D., et al. Altered microRNA expression in human heart disease. Physiol Genomics 2007;31:367–373. 7. Zhao, Y., Ransom, J.F., Li, A, Vedantham V, Von Drehle M, Muth A,N., et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-12. Cell 2007;129:303–317. 8. Thum, T., Catalucci, D., Bauersachs, J., MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 2008;79:562–570. 9. Bartel, D. P., MicroRNAs:genomics, biogenesis, mechanism,and function. Cell 2004. 116, 281–297. 10. Peng, Y., Song, L., Zhao, M., et al.: Criticalroles of miRNA-mediated regulation of TGFb signalling during mousecardiogenesis. Cardiovasc Res. 2014;103(2):258-67 11. Small EM, Olson EN.: Pervasive roles of microRNAs in cardiovascular biol-ogy. Nature. 2011;469(7330):336-42. 12. Thum T, Catalucci D, Bauersachs J.: MicroRNAs: novel regulators in car-diac development and disease. Cardiovasc Res. 2008;79(4):562-70 13. Dangwal, S., Bang, C., Thum, T., :Novel techniques and targets in cardio-vascular microRNA research. Cardiovasc Res. 2012;93(4):545-54. 14. Nabiałek, E., Wańha, W., Kula, D., Jadczyk, T., Krajewska, M., Kowalówka, A., Dworowy, S., Hrycek, E., Włudarczyk, W., Parma, Z., Michalewska-Włudarczyk, A., Pawłowski, T., Ochała, B., Jarząb, B., Tendera, M., Wojakowski, W., Circulating microRNAs (miR-4235p, miR-208a and miR-1) in acute myocardial infarction and stable coronary heart disease. Minerva Cardioangiol 2013; 61: 627-37. 15. Lee, R.C., Feinbaum, R.L. and Ambros V. The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854 16. G.M. Borchert, W. Lanier, B.L. Davidson, RNA polymerase III transcribes human microRNAs, Nat. Struct. Mol. Biol. 13 (2006) 1097e1101 17. J. Krol, I. Loedige, W., Filipowicz, The widespread regulation of microRNAbiogenesis, function and decay, Nat. Rev. Genet. 11 (2010) 597e610 18. Cai, X., Hagedorn C.H., Cullen, B.R., Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs.RNA. 2004;10:1957–1966. 19. Lee, Y., Kim, M., Han, J., Yeom K.H., Lee, S., Baek S.H., Kim, V.N., Micro RNAgenes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–4060.
CE
PT
ED
M
AN
US
CR
IP
T
6.
20. Denli, A.M., Tops, B.B., Plasterk, R.H., Ketting, R.F., Hannon, G.J., Processing ofprimary
AC
microRNAs by the Microprocessor complex. Nature. 2004;432:231–235. 21. Gregory, R.I., Yan, K.P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N.,
Shiekhattar, R,. The Microprocessor complex mediates the genesis of microRNAs.
Nature. 2004;432:235–240. 22. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., RadmarkO, Kim,
S., Kim, V.N., The nuclear RNase III Drosha initiates microRNAprocessing. Nature. 2003;425:415–419. 23. Yi, R., Qin, Y., Macara, I.G., Cullen, B.R., Exportin-5 mediates the nuclearexport of premicroRNAs and short hairpin RNAs. Genes Dev. 2003;17:3011–3016.
ACCEPTED MANUSCRIPT 24. Chendrimada, T.P., Gregory, R.I., Kumaraswamy, E., Norman, J., Cooch, N,,Nishikura K,
25. 26.
CR
US
29.
IP
T
27.
Shiekhattar R. TRBP recruits the Dicer complex to Ago2 formicroRNA processing and gene silencing. Nature. 2005;436:740–744. Khvorova, A., Reynolds, A., Jayasena S.D., Functional siRNAs and miRNAsexhibit strand bias. Cell. 2003;115:209–216. Cheloufi, S, Dos Santos C.O., Chong, M.M., Hannon G.J., A dicer independent miRNA biogenesis pathway that requires Ago catalysis.Nature. 2010;465:584–589. Zampetaki A, Willeit P, Tilling L, et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012;60:290–9. 28. Devaux, Y., Vausort, M., McCann G.P., et al. A panel of 4 microRNAs facilitates theprediction of left ventricular contractility after acute myocardial infarction. PLoS ONE 2013;8:e70644 T. Alexy, K. Rooney,M. Weber et al., “TNF-𝛼 alters the releaseand transfer of microparticle -encapsulated miRNAs fromendothelial cells,” Physiological Genomics, vol. 46, pp. 8330,2014 30. S. Dangwal, C. Bang, and T. Thum, “Novel techniques andtargets in cardiovascular microRNA research,” CardiovascularResearch, vol. 93, no. 4, pp. 545–554, 2012.
31. S, Kumar, C. W, Kim, R. D. Simmons et al., “Role of flowsensitivemicroRNAs in
M
AN
endothelial dysfunction and atherosclerosis:mechanosensitive athero-miRs,” Arteriosclerosis,Thrombosis, and Vascular Biology, vol. 34, pp. 2206–2216, 2014
32. Chen, K.C., Wang Y.S., Hu, C.Y., Chang, W.C., Liao, Y.C., Dai ,C.Y., Juo S.H., Oxldl up-
PT
ED
regulates microrna-29b, leading to epigenetic modifications of mmp-2/mmp-9 genes: A novel mechanism for cardiovascular diseases. Faseb J. 2011; 25 (5):1718–1728. doi:1710.1096/fj.1710-174904. Epub 172011 Jan 174925. Identified miRNA-29b as modifying MMP activity. [PubMed: 21266537]. 33. Lu, Y., Zhang, Y., Wang, N., et al. MicroRNA-328 contributes to adverse electricalremodeling in atrial fibrillation. Circulation 2010;122:2378–87.
CE
34. Fichtlscherer, S., De Rosa S., Fox, H., Schwietz, T., Fischer, A., Liebetrau ,C., et al.
Circ
Res.
AC
Circulating microRNAs in patients with coronary artery disease. 2010;107(5):677-84, http://dx.doi.org/10.1161/CIRCRESAHA.109.215566.
35. D’Alessandra, Y., Carena, M.C., Spazzafumo, L., Martinelli, F., Bassetti, B., Devanna P, et
al. Diagnostic potential of plasmatic MicroRNA signatures in stable and unstable angina. PLoS One. 2013;8(11):e80345, http://dx. doi.org/10.1371/journal.pone.0080345 36. Wu, C., Gong, Y., Sun, A., Zhang, Y., Zhang, C., Zhang ,W., et al. The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding. Nutr Metab Cardiovasc Dis. 2013; 23(7):693-8, http://dx.doi.org/10.1016/j.numecd.2012.02.009 37. Wang, R., Li, N., Zhang, Y., et al. CirculatingmicroRNAs are promising novel
biomarkersof acute myocardial infarction. Intern Med.2011; 50: 1789–95 38. X. Ji, R. Takahashi, Y. Hiura, G. Hirokawa, Y. Fukushima, N. Iwai, Plasma miR208 as a
biomarker of myocardial injury, Clin. Chem. 55 (2009) 1944e1949.
ACCEPTED MANUSCRIPT 39. Olivieri, F., Antonicelli, R., Lorenzi, M., et al .Diagnostic potential of circulating miR-
T
4995p in elderly patients with acute non ST-ele-vation myocardial infarction. Int J Cardiol.2013; 167: 531–6. 40. B. Meder., A. Keller., B. Voge.l, et al.: MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction, Basic Res. Cardiol. 2011; 106 41. Eitel. I., Adams, V., Dieterich, P., et al.: Relation of circulating MicroRNA-133a concentrations with myocardial damage and clinical prognosis in ST-elevation myocardial infarction. Am Heart J. 2012; 164: 706–14. 42. Bauters, C., Kumarswamy, R., Holzmann, A. ,et al.:Circulating miR-133a and miR-423-
CR
IP
5pfail as biomarkers for left ventricular remodeling after myocardial infarction. Int JCardiol. 2013;12:074.
43. M.S. Ebert, J.R. Neilson, P.A. Sharp,: MicroRNA sponges: competitive inhibitors of
US
smallRNAs in mammalian cells, Nat. Methods 2007; 4 :721e726
44. Li, J., Xu, J., Cheng, Y., Wang, F., Song Y, Xiao J., Circulating microRNAs as mirrors of
AC
CE
PT
ED
M
AN
acute coronary syndromes: MiRacle or quagMire? J Cell Mol Med. 2013 Nov;17(11):136370. doi: 10.1111/jcmm.12148. Epub 2013 Nov 4. Review. PubMed [citation] PMID: 24188699, PMCID: PMC4117549
ACCEPTED MANUSCRIPT
Highlights
CE
PT
ED
M
AN
US
CR
IP
T
miRNA play key role in cell signalling pathways in CVDs. miRNA affect on post-translational activity of the gene. Circulating miRNA can be used as potential biomarker in prognosis of cardio vascular diseases.
AC
ACCEPTED MANUSCRIPT
CAD
Coronary artery disease
CVD
Cardio Vascular Disease ST elevation myocardial infarction
NSTEMI
Non-ST elevation myocardial infarction
MI
Myocardial infarction
ACS
Acute coronary syndrome
CHD
Coronary heart disease
TNF-α
Tumor Necrosis factor MicroRNAs
unstable angina
AC
CE
PT
ED
UA
M
miRNAs
AN
US
CR
IP
STEMI
T
Abbreviations list
Reena Kumari, Sandeep Kumar, Ravikant PII: DOI: Reference:
S2452-0144(18)30124-9 doi:10.1016/j.genrep.2018.10.003 GENREP 327
To appear in:
Gene Reports
Received date: Revised date: Accepted date:
30 May 2018 21 September 2018 5 October 2018
Please cite this article as: Reena Kumari, Sandeep Kumar, Ravikant , The role of circulating miRNAs in the pathophysiology of CVD: As a potential biomarker. Genrep (2018), doi:10.1016/j.genrep.2018.10.003
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Review Article The role of Circulating miRNAs in the pathophysiology of CVD: As a potential biomarker Reena Kumari*1,2 , Sandeep Kumar*3 and Ravikant4
IP
T
1. Department of Zoology University of Lucknow, Lucknow
CR
2. Department of Biochemistry, King George’s Medical University, Lucknow-226003
M
AN
4. Department of General Surgery, AIIMS, Rishikesh
US
3. Department of Biochemistry, AIIMS, Rishikesh
AC
CE
PT
Dr. Reena Kumari Research Associate Department of Biochemistry KGMU, Lucknow [email protected]
ED
*Address to correspondence:
Conflict of Interest: - None
Dr. Sandeep Kumar Demonstrator Department of Biochemistry AIIMS, Rishikesh
[email protected]
ACCEPTED MANUSCRIPT Abstracts- Cardio Vascular Disease (CVD) has raised morbidity and mortality rate in near future and also remains a major financial burden in most developed countries around the world wide. According to World Health Organization (WHO) an estimated 17.5 million people died each year by CVD and more than 75 percent of CVD deaths are due to heart attacks and
T
strokes. Approximately half of these deaths are mostly occur in adults and middle aged person.
IP
In past few years specific Micro RNAs (miRNA) expression patterns have been regulates the
CR
various medical conditions and which are associated in the development of CVD. These miRNAs are small, non-coding, RNA molecules approximately 22 nucleotides in length which
US
regulate a large fraction of genome by binding to complementary messenger RNA sequences,
AN
resulting in translational repression and gene silencing and are also found in all eukaryotic cells. To date approximately 2200 miRNA genes have been reported to exist in the mammalian
M
genome from which over 1000 belong to the human genome. miRNAs have been involved in
ED
inter cellular communication and have been shown to circulate in the blood stream in cell free forms. Individual miRNAs have been shown to regulate the expression of multiple genes.
PT
Conversely, the expression of individual genes can be regulated by multiple miRNAs.
CE
Therefore, In the present study we have aimed to investigate the role of miRNAs in the pathophysiology of CVD. Conclusively we have found that these miRNAs are play as potential
AC
biomarkers in early diagnosis and therapeutic targets for CVD.
Keywords: miRNA, CVD, Pathophysiology, Progression
ACCEPTED MANUSCRIPT 1.
Introduction-
Cardiovascular diseases, mainly coronary artery diseases (CAD) which are posing a high socioeconomic burden on the health worldwide [1], of all 60 million cases of deaths from all causes worldwide in 2005, an estimated 18 million were due to cardiovascular diseases, three
T
times more than caused by infectious diseases including HIV/AIDS, tuberculosis, and malaria
IP
combined [2]. MicroRNAs are important post-transcriptional regulators of genes. In humans,
CR
about one-third of the genes are regulated by microRNAs, which suggests an important
US
regulatory role of microRNAs in gene expression and hence phenotype determination [3]. It is estimated that the human genome encodes approximately 1000 miRNAs. Among them, more
AN
than 100 have been identified in sera from healthy subjects and are designated circulating miRNAs. Unlike intracellular mRNAs, circulating miRNAs show remarkable stability and
M
resistance to degradation by endogenous RNase activity. The majority of the circulating
ED
miRNAs are derived from blood cells with others from various tissues such as heart, lung, liver
PT
and kidney. The stability of circulating miRNAs has stimulated interest in their use as biomarkers for the diagnosis and prognosis of various diseases including CVD [4]. Most
CE
miRNAs differ in temporal or spatial expression patterns in the body, such as miR-1/miR133, which are specifically expressed in muscles [5]. These tiny molecules show tremendous gene
AC
regulatory potential and play a key role in pathophysiology of almost all organs, including the cardiovascular system [6] and Changes in miRNA expression profiles are noted during cardiogenesis as well as progression of heart diseases, indicating miRNA deregulation to be mechanistically involved in cardiovascular pathologies [6,7,8] miRNAs are a group of noncoding regulatory RNAs and participate in a surprisingly diverse collection of regulatory events. which are a family of about 22 nucleotides that control gene expression at the post-
ACCEPTED MANUSCRIPT transcriptional level [9]. It is well established that miRNAs play critical roles in the physiological and pathological processes in cardiovascular system, such as endothelial dysfunction, inflammation, apoptosis, angiogenesis, atherosclerosis [10-13] and also play crucial role in cell differentiation, cell growth, mobility and apoptosis.
IP
T
2. The biogenesis of miRNAs
MicroRNAs (miRNAs) are endogenous small non-coding RNAs with 21-25 nucleotides in
CR
length. By pairing with the 3’ UTR of target mRNAs, miRNAs can regulate protein-coding
US
genes at the posttranscriptional level via degradation of mRNAs or repression of protein translation [14]. The first micro RNA was discovered in nematode Caenorhabditis elegans by
AN
the Ambros group at Harvard University in 1993 [15]. The biogenesis of miRNA are governed
M
by several regulatory check points, generally the miRNAs are transcribed by RNA polymerase II and infrequently by RNA polymerase III [16], miRNAs are derive from noncoding transcripts
ED
which are also co-expressed with the host gene transcript or located in intergenic regions of the
PT
genome. The primary miRNA transcripts are transcribed as the precursor molecules known as pri-miRNAs which are contain a canonical hairpin structure, a 50 cap and a 30 poly-A tail [17],
CE
derived either from annotate transcripts or from intergenic regions within the genome and can
AC
predetermine a single or multiple miRNAs [18,19]. Pri-miRNAs fold into hairpin structures containing improperly base-paired stems and which are transcripts in the nucleus by the Drosha complex and processed into 60 to 100 nucleotides hairpins known as pre-miRNAs [20-22] after that it is exported from the nucleus to the cytoplasm by exportin 5 [23], and usually cleaved by the endonuclease Dicer and give up imperfect miRNA-miRNA duplexes [24]. These miRNAmiRNA duplexes are converted into a mature miRNA. However, most often the miRNA strand is degraded and incorporated into RNA-induced silencing complex (RISC) and these complex
ACCEPTED MANUSCRIPT are recognizing by particular targets and promote the post-transcriptional gene silencing [25] which carries out the regulatory function of miRNAs by the binding of the target mRNA and either promoting its degradation or inhibiting its translation. Moreover, an alternative biogenesis pathway was currently discovered in which miR-451 enters RISC by direct loading
T
of the pre-miR into RISC after Drosha processing, by skipping further processing by Dicer [26]
AC
CE
PT
ED
M
AN
US
CR
IP
(Figure 1).
Figure1: The schematic representation of biogenesis of miRNA
ACCEPTED MANUSCRIPT 3. miRNA in CVD progression and development Cardio vascular Disease is a clinical diagnosis when the heart fails to provide sufficient circulatory force to meet the body’s metabolic requirements. It is one of the major causes of mortality in the US, responsible for ~30% of patient deaths annually and also in other
T
developing countries like India. Heart failure is the final manifestation of CVD and cardiac
IP
injury, as well as less common but important etiologies including cardiomyopathies, valvular
CR
heart disease, prolonged arrhythmias, myocarditis, infections and exposure to cardiotoxic drugs circulating miRNAs have been identified as potential biomarkers of CVDs [4]. miRNA are play
US
key role in the pathophysiology of CVD progression and development which are regulate gene
AN
expression of mature mRNA at the post transcriptional level during transcript degradation or translational suppression by binding to the 3’ UTR of the target mRNA so that we can say each
M
miRNA have hundreds of target mRNAs for its permissive binding state of mRNA, signifying
ED
that an each mRNA is regulated by several miRNAs and several miRNA regulates more than one mRNAs and which are constitute a new class of distinctive molecular regulators involved
PT
in the pathophysiology of miRNAs comprise a new class of unique molecular regulators
CE
involved in the pathophysiology of CVD. miRNAs play significant roles in CVD development and also their expression profile changes according to different pathological conditions.
AC
Previous studies have suggested that the evaluated miRNAs have been identified in cardiac tissue at all stages of development and it is now acknowledged that miRNAs are involved in nearly all forms of CVDs. We have discussed the role of miRNA in many forms of CVDs. (a). Circulating miRNAs and AtherosclerosisAtherosclerosis, are a condition where the arteries become hardened and narrowed due to an excessive deposite of plaque inside the arteries. Plaque is made of cholesterol, cellular waste
ACCEPTED MANUSCRIPT products, calcium, fatty substances and fibrin (a clotting material in the blood). Previous studies have investigated the role of miRNAs in development of atherosclerosis. Many miRNAs are directly or indirectly regulate endothelial dysfunction (ECs), lipid dysregulation, infiltration of inflammatory cells and vascular smooth muscle cell (VSMC) differentiation through their
T
specific miRNA-155 play a key role in to the infiltration of inflammatory cells and their
IP
permeability increased by ECs [27, 28]. miRNAs are also a key regulatory molecules in
CR
platelets, immune cells, VSMC, and ECs which are responsible to the initiation and progression of atherosclerosis and ECs [29]. It has been reveals a range of miRNAs like as (miR-10a, miR-
US
19a, miR-23b, miR-17-92, miR-21, miR-24, miR-92a, miR-101, miR-126, miR-145, miR-155,
AN
miR205, miR-663, and miR-712 are highly significantly expressed in atherosclerosis, angiogenesis, and arterial remodeling [30, 31]. Although, MMPs associated to atherosclerotic
M
plaque progression, destabilization, and Oxidized LDL, plays a crucial role in atherosclerosis,
PT
migration of VSMC [32].
ED
through increases miRNA-29b expression in MMP-2 and MMP-9 which are increases the
CE
(b). Circulating miRNAs and arrhythmiasAn arrhythmia describes an irregular heartbeat it is also called Atrial fibrillation. There are two
AC
basic kinds of arrhythmias one is Bradycardia, when the heart beat too slow- less than 60 beats per minute and second is called tachycardia when the heart may beat too fast more than 100 beats per minute. The circulating level of miR-328 are highly elevated 3.5 fold in atrial fibrillation patients in comparison to without AF person and the level of miR-223 and miR-664 were also elevated in AF but most interestingly, miR-1 was unaffected [33].
ACCEPTED MANUSCRIPT (c). Circulating miRNAs and Coronary artery disease Coronary artery disease also called coronary heart diseases is a common term for the buildup of plaque in the heart’s arteries that could lead to heart attack. The various number of miRNAs have been linked to a diagnosis of coronary artery disease. Some studies have been associated
IP
T
with potential role of miRNA in CAD patients. The Circulating levels of miR-1, miR-122,
CR
miR-133a, miR-133b miR-208a, miR-337-5p, miR-433, and miR-485-3p were significantly upregulated, whereas miR-17, miR-92a, miR-126, miR-145, miR-155, and miR-199a levels were
US
markedly down-regulated in CAD [34, 35]. The Previous studies showed that the circulating level of miR-424 and miR-149 in plasma were significantly down-regulated, while the level of
AN
miR-765 in plasma were up-regulated in stable and unstable CAD patients compared with
M
healthy control. The values of AUC (area under the curve) for miR-149, miR-424 and miR-765 were significantly increases in stable CAD patients (0.938, 0.919 and 0.968, respectively) and
ED
in unstable CAD patients (0.951, 0.960 and 0.977, respectively) compared with healthy control.
PT
previous results showed that the plasma level of miR-149 and miR-424 were significantly down-regulated, whereas plasma level of miR-765 were up-regulated in stable and unstable
CE
CAD patients compared with healthy control [36].
AC
(d). Circulating miRNAs and Acute coronary syndromes Acute coronary syndrome denotes a range of disorders, including a heart attack (myocardial infarction) and unstable angina, which are caused by the same underlying problems. According to the Cardiologists, the ACS divided into three distinct clinical patterns in which two of them represent different forms of MI like as ST-Elevation myocardial infarction (STEMI) & NonST-Elevation myocardial infarction (NSTEMI) and another one represents a severe form of
ACCEPTED MANUSCRIPT angina, called "unstable angina these all three are caused by acute blood clots in the coronary arteries. The circulating miRNAs are a new biomarker for ACS and play an important role in diagnosis, prediction, prognosis and reaction in ACS patients the outline of circulating miRNAs as the diagnostic biomarkers for ACS [37]. Previous study shows that the levels of six miRNAs
T
like as miR-208a, miR-499, miR-499-5p miR-1, miR-133a, miR-133b, in 224 AMI patients out
IP
of which the level of miR-208b, miR-320a and miR-499-5p were found significantly higher in
CR
Acute myocardial infarction patients compared to healthy controls [38]. Several miRNAs are
US
responsible for the diagnosis of different forms of ACS which are follows as- (Figure-2) (i). Unstable Angina (UA)- Circulating level of miR-1, miR-122, miR-126, miR-133a/b, miR-
AN
199a, miR-485-3p were all upregulated in stable form and unstable angina, even as the
M
circulating level of miR-145 was significantly elevated only in unstable angina [36]. (ii). Non-ST-Elevation Myocardial Infarction (NSTEMI)- In a very recent study, the level
ED
of miRNA-499-5p was elevated in plasma of NSTEMI patients and to be reported that The
PT
diagnostic accuracy of miRNA-499-5p was even higher than conventional and high-sensitivity cTnT (hs-cTnT) in differentiating NSTEMI form of ACS [39].
CE
(iii). ST-Elevation Myocardial Infarction (STEMI)- miR-133a level are elevated in STEMI
AC
forms and shows up-regulated and also observed significant correlations with ACS [40], miR30c and miR-145 were also positively up-regulated in STEMI Forms [41, 42].
M
AN
US
CR
IP
T
ACCEPTED MANUSCRIPT
ED
Figure 2: Overview of circulating microRNAs in acute coronary syndrome. Unstable angina; NSTEMI: Non-ST- segment elevated myocardial infarction; STEMI: ST segment elevated myocardial infarction.
PT
4. miRNA modulation as a therapeutic approach challenges
CE
According to the previous studies, the miRNA plays a key role in gene regulation and provide promising therapeutic targets but currently The biggest challenge here lies in the capability to
AC
predict the accurate results due to It is accepted that micro RNAs are not specific for their regulation of a single gene. actually, they can modulate hundreds of target genes and causes effects of miRNA modulation in the human body [43]. circulating micro RNAs can play a diagnostic or prognostic purposes in cardiovascular disease and which are described an approach in which micro RNA function was blocked by scavenging away from the miRNA and they are called “miRNA sponges” and these miRNA sponges Possessing multiple binding sites,
ACCEPTED MANUSCRIPT through the bind up to a programmed RNA-induced silencing complex and reducing its availability and effective function of entire micro RNA families [44]. 5. ConclusionConclusively, we have found that circulating miRNAs have emerged as novel promising
T
biomarkers for cardio vascular diseases including its role in diagnosis, prediction, prognosis and
IP
reaction to therapy. So present study reveals that these miRNAs play a key role in development
CR
of cardiovascular disease and may be used as a potential biomarker for early detection of cardio vascular disease like myocardial infarction. Further study will be needed to explore the role of
AN
pathophysiology of cardiovascular diseases.
US
these miRNAs in the mechanistic view on different metabolic pathway which is involved in the
6. Conflicts of interest- The authors declare that there is no conflict of interests regarding the
ED
M
publication of this paper.
PT
References:-
Nishiguchi, Toshio Imanishi, and Takashi Akasaka: MicroRNAs and Cardiovascular Diseases BioMed Research InternationalVolume 2015; 14 Health Organization,(2013). CardiovascularDiseases. http://www.who.int/cardiovascular_ diseases/en/ [accessedMarch27, 2013].
3.
Availableat:
AC
2. World
CE
1. Tsuyoshi
Paneru, B.,D., Al-Tobasei, R., Kenney, B., Leeds, T.D., Salem, M,. RNA-Seq reveals icroRNA expression signature and genetic polymorphism associated with growth and muscle quality traits in rainbow trout. Sci Rep. 2017 Aug 22;7(1):9078.
4. Zhou, S.S., Jin, J.P., Wang, J.Q., Zhang, Z.G., Freedman, J.H., Zheng, Y., Cai L. miRNAS
in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges. Acta Pharmacol Sin. 2018 Jul;39(7):1073-1084. Mattick, J.S., Makunin I.V., Small regulatory RNAs in mammals. Hum Mol Genet 2005;14Spec No 1:R121–R132. 5.
ACCEPTED MANUSCRIPT Ikeda, S., Kong, S.W., Lu, J., Bisping, E., Zhang, H., Allen, P. D., et al. Altered microRNA expression in human heart disease. Physiol Genomics 2007;31:367–373. 7. Zhao, Y., Ransom, J.F., Li, A, Vedantham V, Von Drehle M, Muth A,N., et al. Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-12. Cell 2007;129:303–317. 8. Thum, T., Catalucci, D., Bauersachs, J., MicroRNAs: novel regulators in cardiac development and disease. Cardiovasc Res 2008;79:562–570. 9. Bartel, D. P., MicroRNAs:genomics, biogenesis, mechanism,and function. Cell 2004. 116, 281–297. 10. Peng, Y., Song, L., Zhao, M., et al.: Criticalroles of miRNA-mediated regulation of TGFb signalling during mousecardiogenesis. Cardiovasc Res. 2014;103(2):258-67 11. Small EM, Olson EN.: Pervasive roles of microRNAs in cardiovascular biol-ogy. Nature. 2011;469(7330):336-42. 12. Thum T, Catalucci D, Bauersachs J.: MicroRNAs: novel regulators in car-diac development and disease. Cardiovasc Res. 2008;79(4):562-70 13. Dangwal, S., Bang, C., Thum, T., :Novel techniques and targets in cardio-vascular microRNA research. Cardiovasc Res. 2012;93(4):545-54. 14. Nabiałek, E., Wańha, W., Kula, D., Jadczyk, T., Krajewska, M., Kowalówka, A., Dworowy, S., Hrycek, E., Włudarczyk, W., Parma, Z., Michalewska-Włudarczyk, A., Pawłowski, T., Ochała, B., Jarząb, B., Tendera, M., Wojakowski, W., Circulating microRNAs (miR-4235p, miR-208a and miR-1) in acute myocardial infarction and stable coronary heart disease. Minerva Cardioangiol 2013; 61: 627-37. 15. Lee, R.C., Feinbaum, R.L. and Ambros V. The C.elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 1993; 75: 843-854 16. G.M. Borchert, W. Lanier, B.L. Davidson, RNA polymerase III transcribes human microRNAs, Nat. Struct. Mol. Biol. 13 (2006) 1097e1101 17. J. Krol, I. Loedige, W., Filipowicz, The widespread regulation of microRNAbiogenesis, function and decay, Nat. Rev. Genet. 11 (2010) 597e610 18. Cai, X., Hagedorn C.H., Cullen, B.R., Human microRNAs are processed fromcapped, polyadenylated transcripts that can also function as mRNAs.RNA. 2004;10:1957–1966. 19. Lee, Y., Kim, M., Han, J., Yeom K.H., Lee, S., Baek S.H., Kim, V.N., Micro RNAgenes are transcribed by RNA polymerase II. EMBO J. 2004;23:4051–4060.
CE
PT
ED
M
AN
US
CR
IP
T
6.
20. Denli, A.M., Tops, B.B., Plasterk, R.H., Ketting, R.F., Hannon, G.J., Processing ofprimary
AC
microRNAs by the Microprocessor complex. Nature. 2004;432:231–235. 21. Gregory, R.I., Yan, K.P., Amuthan, G., Chendrimada, T., Doratotaj, B., Cooch, N.,
Shiekhattar, R,. The Microprocessor complex mediates the genesis of microRNAs.
Nature. 2004;432:235–240. 22. Lee, Y., Ahn, C., Han, J., Choi, H., Kim, J., Yim, J., Lee, J., Provost, P., RadmarkO, Kim,
S., Kim, V.N., The nuclear RNase III Drosha initiates microRNAprocessing. Nature. 2003;425:415–419. 23. Yi, R., Qin, Y., Macara, I.G., Cullen, B.R., Exportin-5 mediates the nuclearexport of premicroRNAs and short hairpin RNAs. Genes Dev. 2003;17:3011–3016.
ACCEPTED MANUSCRIPT 24. Chendrimada, T.P., Gregory, R.I., Kumaraswamy, E., Norman, J., Cooch, N,,Nishikura K,
25. 26.
CR
US
29.
IP
T
27.
Shiekhattar R. TRBP recruits the Dicer complex to Ago2 formicroRNA processing and gene silencing. Nature. 2005;436:740–744. Khvorova, A., Reynolds, A., Jayasena S.D., Functional siRNAs and miRNAsexhibit strand bias. Cell. 2003;115:209–216. Cheloufi, S, Dos Santos C.O., Chong, M.M., Hannon G.J., A dicer independent miRNA biogenesis pathway that requires Ago catalysis.Nature. 2010;465:584–589. Zampetaki A, Willeit P, Tilling L, et al. Prospective study on circulating microRNAs and risk of myocardial infarction. J Am Coll Cardiol 2012;60:290–9. 28. Devaux, Y., Vausort, M., McCann G.P., et al. A panel of 4 microRNAs facilitates theprediction of left ventricular contractility after acute myocardial infarction. PLoS ONE 2013;8:e70644 T. Alexy, K. Rooney,M. Weber et al., “TNF-𝛼 alters the releaseand transfer of microparticle -encapsulated miRNAs fromendothelial cells,” Physiological Genomics, vol. 46, pp. 8330,2014 30. S. Dangwal, C. Bang, and T. Thum, “Novel techniques andtargets in cardiovascular microRNA research,” CardiovascularResearch, vol. 93, no. 4, pp. 545–554, 2012.
31. S, Kumar, C. W, Kim, R. D. Simmons et al., “Role of flowsensitivemicroRNAs in
M
AN
endothelial dysfunction and atherosclerosis:mechanosensitive athero-miRs,” Arteriosclerosis,Thrombosis, and Vascular Biology, vol. 34, pp. 2206–2216, 2014
32. Chen, K.C., Wang Y.S., Hu, C.Y., Chang, W.C., Liao, Y.C., Dai ,C.Y., Juo S.H., Oxldl up-
PT
ED
regulates microrna-29b, leading to epigenetic modifications of mmp-2/mmp-9 genes: A novel mechanism for cardiovascular diseases. Faseb J. 2011; 25 (5):1718–1728. doi:1710.1096/fj.1710-174904. Epub 172011 Jan 174925. Identified miRNA-29b as modifying MMP activity. [PubMed: 21266537]. 33. Lu, Y., Zhang, Y., Wang, N., et al. MicroRNA-328 contributes to adverse electricalremodeling in atrial fibrillation. Circulation 2010;122:2378–87.
CE
34. Fichtlscherer, S., De Rosa S., Fox, H., Schwietz, T., Fischer, A., Liebetrau ,C., et al.
Circ
Res.
AC
Circulating microRNAs in patients with coronary artery disease. 2010;107(5):677-84, http://dx.doi.org/10.1161/CIRCRESAHA.109.215566.
35. D’Alessandra, Y., Carena, M.C., Spazzafumo, L., Martinelli, F., Bassetti, B., Devanna P, et
al. Diagnostic potential of plasmatic MicroRNA signatures in stable and unstable angina. PLoS One. 2013;8(11):e80345, http://dx. doi.org/10.1371/journal.pone.0080345 36. Wu, C., Gong, Y., Sun, A., Zhang, Y., Zhang, C., Zhang ,W., et al. The human MTHFR rs4846049 polymorphism increases coronary heart disease risk through modifying miRNA binding. Nutr Metab Cardiovasc Dis. 2013; 23(7):693-8, http://dx.doi.org/10.1016/j.numecd.2012.02.009 37. Wang, R., Li, N., Zhang, Y., et al. CirculatingmicroRNAs are promising novel
biomarkersof acute myocardial infarction. Intern Med.2011; 50: 1789–95 38. X. Ji, R. Takahashi, Y. Hiura, G. Hirokawa, Y. Fukushima, N. Iwai, Plasma miR208 as a
biomarker of myocardial injury, Clin. Chem. 55 (2009) 1944e1949.
ACCEPTED MANUSCRIPT 39. Olivieri, F., Antonicelli, R., Lorenzi, M., et al .Diagnostic potential of circulating miR-
T
4995p in elderly patients with acute non ST-ele-vation myocardial infarction. Int J Cardiol.2013; 167: 531–6. 40. B. Meder., A. Keller., B. Voge.l, et al.: MicroRNA signatures in total peripheral blood as novel biomarkers for acute myocardial infarction, Basic Res. Cardiol. 2011; 106 41. Eitel. I., Adams, V., Dieterich, P., et al.: Relation of circulating MicroRNA-133a concentrations with myocardial damage and clinical prognosis in ST-elevation myocardial infarction. Am Heart J. 2012; 164: 706–14. 42. Bauters, C., Kumarswamy, R., Holzmann, A. ,et al.:Circulating miR-133a and miR-423-
CR
IP
5pfail as biomarkers for left ventricular remodeling after myocardial infarction. Int JCardiol. 2013;12:074.
43. M.S. Ebert, J.R. Neilson, P.A. Sharp,: MicroRNA sponges: competitive inhibitors of
US
smallRNAs in mammalian cells, Nat. Methods 2007; 4 :721e726
44. Li, J., Xu, J., Cheng, Y., Wang, F., Song Y, Xiao J., Circulating microRNAs as mirrors of
AC
CE
PT
ED
M
AN
acute coronary syndromes: MiRacle or quagMire? J Cell Mol Med. 2013 Nov;17(11):136370. doi: 10.1111/jcmm.12148. Epub 2013 Nov 4. Review. PubMed [citation] PMID: 24188699, PMCID: PMC4117549
ACCEPTED MANUSCRIPT
Highlights
CE
PT
ED
M
AN
US
CR
IP
T
miRNA play key role in cell signalling pathways in CVDs. miRNA affect on post-translational activity of the gene. Circulating miRNA can be used as potential biomarker in prognosis of cardio vascular diseases.
AC
ACCEPTED MANUSCRIPT
CAD
Coronary artery disease
CVD
Cardio Vascular Disease ST elevation myocardial infarction
NSTEMI
Non-ST elevation myocardial infarction
MI
Myocardial infarction
ACS
Acute coronary syndrome
CHD
Coronary heart disease
TNF-α
Tumor Necrosis factor MicroRNAs
unstable angina
AC
CE
PT
ED
UA
M
miRNAs
AN
US
CR
IP
STEMI
T
Abbreviations list