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Human coronary heart disease: importance of blood cellular miR-2909 RNomics

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Abstract

The characterization of atherosclerosis as a chronic inflammatory disease has triggered extensive research worldwide to dissect the pro- and anti-inflammatory, cellular as well as molecular mechanisms governing the pathogenesis of this dreadful disease. Though several microRNAs have been shown to play crucial role in regulating lipid metabolism and inflammation, we are far from resolving the role of epigenomic signals in etiology of coronary heart disease (CHD). The present study was addressed to understand the role of a novel microRNA, miR-2909, in the regulation of genes involved in the initiation and progression of human coronary occlusion. Peripheral blood mononuclear cells were isolated from human CHD subjects at various stages of coronary occlusion (n = 80) and their corresponding normal healthy counterparts (n = 20). Various experimental strategies involving gene expression and silencing, reporter plasmid assays, and flow cytometric analysis were blend together to address the current problem. The present study shows for the first time that the blood cellular miR-2909 expression increases with the severity of coronary occlusion, exhibiting a strong positive correlation (r = 0.943 at p < 0.01). Further, miR-2909 was shown to regulate genes involved in inflammation, immunity, and oxLDL uptake, thereby contributing significantly to the initiation and progression of CHD patho-physiological process. Based upon these results, we propose that miR-2909 RNomics may be a step forward in understanding human CHD at the epigenomic level and can be exploited for designing new therapeutic strategies as well as diagnostic and prognostic markers for this disease in future.

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References

  1. Kutuk O, Basaga H (2003) Inflammation meets oxidation: NF-kappaB as a mediator of initial lesion development in atherosclerosis. Trends Mol Med 9:549–557

    Article  CAS  PubMed  Google Scholar 

  2. Michael DR, Ashlin TG, Buckley ML, Ramji DP (2012) Liver X receptors, atherosclerosis and inflammation. Curr Atheroscler Rep 14:284–293

    Article  CAS  PubMed  Google Scholar 

  3. Zelcer N, Tontonoz P (2006) Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116:607–614

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Joseph SB, Castrillo A, Laffitte BA, Mangelsdorf DJ, Tontonoz P (2003) Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 9:213–219

    Article  CAS  PubMed  Google Scholar 

  5. de Winther MP, Kanters E, Kraal G, Hofker MH (2005) Nuclear factor kappaB signaling in atherogenesis. Arterioscler Thromb Vasc Biol 25:904–914

    Article  PubMed  Google Scholar 

  6. Ross R (1999) Atherosclerosis—an inflammatory disease. N Engl J Med 340:115–126

    Article  CAS  PubMed  Google Scholar 

  7. Dave VP, Kaul D, Sharma Y, Bhattacharya R (2009) Functional genomics of blood cellular LXR-alpha gene in human coronary heart disease. J Mol Cell Cardiol 46:536–544

    Article  CAS  PubMed  Google Scholar 

  8. Madrigal-Matute J, Rotllan N, Aranda JF, Fernandez-Hernando C (2013) MicroRNAs and atherosclerosis. Curr Atheroscler Rep 15:322

    Article  PubMed  Google Scholar 

  9. Vickers KC, Remaley AT (2010) MicroRNAs in atherosclerosis and lipoprotein metabolism. Curr Opin Endocrinol Diabetes Obes 17:150–155

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Chen KC, Hank Juo SH (2012) MicroRNAs in atherosclerosis. Kaohsiung J Med Sci 28:631–640

    Article  CAS  PubMed  Google Scholar 

  11. Kaul D, Hussain A (2009) Cellular AATF gene encodes a novel miRNA that can contribute to HIV-1 latency. Indian J Biochem Biophys 46:237–240

    CAS  Google Scholar 

  12. Sharma M, Sharma S, Arora M, Kaul D (2013) Regulation of cellular Cyclin D1 gene by arsenic is mediated through miR-2909. Gene 522:60–64

    Article  CAS  PubMed  Google Scholar 

  13. Kaul D, Sasikala M, Raina A (2012) Regulatory role of miR-2909 in cell-mediated immune response. Cell Biochem Funct 30:500–504

    Article  CAS  PubMed  Google Scholar 

  14. Visvikis-Siest S, Marteau JB, Samara A, Berrahmoune H, Marie B, Pfister M (2007) Peripheral blood mononuclear cells (PBMCs): a possible model for studying cardiovascular biology systems. Clin Chem Lab Med 45:1154–1168

    Article  CAS  PubMed  Google Scholar 

  15. Ritchie ME (1998) Nuclear factor-kappaB is selectively and markedly activated in humans with unstable angina pectoris. Circulation 98:1707–1713

    Article  CAS  PubMed  Google Scholar 

  16. World Medical Association (2002) World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects. J Postgrad Med 48:206–208

    Google Scholar 

  17. Gensini GG (1983) A more meaningful scoring system for determining the severity of coronary heart disease. Am J Cardiol 51:606

    Article  CAS  PubMed  Google Scholar 

  18. Rehmsmeier M, Steffen P, Hochsmann M, Giegerich R (2004) Fast and effective prediction of microRNA/target duplexes. RNA 10:1507–1517

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Xuan Z, Zhao F, Wang J, Chen G, Zhang MQ (2005) Genome-wide promoter extraction and analysis in human, mouse, and rat. Genome Biol 6:R72

    Article  PubMed Central  PubMed  Google Scholar 

  20. Bryne JC, Valen E, Tang MH, Marstrand T, Winther O, da Piedade I, Krogh A, Lenhard B, Sandelin A (2008) JASPAR, the open access database of transcription factor-binding profiles: new content and tools in the 2008 update. Nucleic Acids Res 36:D102–D106

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Heinemeyer T, Wingender E, Reuter I, Hermjakob H, Kel AE, Kel OV, Ignatieva EV, Ananko EA, Podkolodnaya OA, Kolpakov FA, Podkolodny NL, Kolchanov NA (1998) Databases on transcriptional regulation: TRANSFAC, TRRD and COMPEL. Nucleic Acids Res 26:362–367

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  22. Boyum A (1968) Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1×g. Scand J Clin Lab Invest Suppl 97:77–89

    CAS  PubMed  Google Scholar 

  23. Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227:680–685

    Article  CAS  PubMed  Google Scholar 

  24. Lowry WE, Richter L, Yachechko R, Pyle AD, Tchieu J, Sridharan R, Clark AT, Plath K (2008) Generation of human induced pluripotent stem cells from dermal fibroblasts. Proc Natl Acad Sci USA 105:2883–2888

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Jono H, Lim JH, Chen LF, Xu H, Trompouki E, Pan ZK, Mosialos G, Li JD (2004) NF-kappaB is essential for induction of CYLD, the negative regulator of NF-kappaB: evidence for a novel inducible autoregulatory feedback pathway. J Biol Chem 279:36171–36174

    Article  CAS  PubMed  Google Scholar 

  26. Hutti JE, Shen RR, Abbott DW, Zhou AY, Sprott KM, Asara JM, Hahn WC, Cantley LC (2009) Phosphorylation of the tumor suppressor CYLD by the breast cancer oncogene IKKepsilon promotes cell transformation. Mol Cell 34:461–472

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Reiley W, Zhang M, Wu X, Granger E, Sun SC (2005) Regulation of the deubiquitinating enzyme CYLD by IkappaB kinase gamma-dependent phosphorylation. Mol Cell Biol 25:3886–3895

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Takami Y, Nakagami H, Morishita R, Katsuya T, Hayashi H, Mori M, Koriyama H, Baba Y, Yasuda O, Rakugi H, Ogihara T, Kaneda Y (2008) Potential role of cylindromatosis (CYLD) as a deubiquitinating enzyme in vascular cells. Am J Pathol 172:818–829

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Kaul D, Baba MI (2005) Genomic effect of vitamin ‘C’ and statins within human mononuclear cells involved in atherogenic process. Eur J Clin Nutr 59:978–981

    Article  CAS  PubMed  Google Scholar 

  30. Baranowski M (2008) Biological role of liver X receptors. J Physiol Pharmacol 59(Suppl 7):31–55

    PubMed  Google Scholar 

  31. Sharma N, Lu Y, Zhou G, Liao X, Kapil P, Anand P, Mahabeleshwar GH, Stamler JS, Jain MK (2012) Myeloid Kruppel-like factor 4 deficiency augments atherogenesis in ApoE−/− mice—brief report. Arterioscler Thromb Vasc Biol 32:2836–2838

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Alaiti MA, Orasanu G, Tugal D, Lu Y, Jain MK (2012) Kruppel-like factors and vascular inflammation: implications for atherosclerosis. Curr Atheroscler Rep 14:438–449

    Article  PubMed  Google Scholar 

  33. Sakai M, Kobori S, Miyazaki A, Horiuchi S (2000) Macrophage proliferation in atherosclerosis. Curr Opin Lipidol 11:503–509

    Article  CAS  PubMed  Google Scholar 

  34. Rekhter MD, Gordon D (1995) Active proliferation of different cell types, including lymphocytes, in human atherosclerotic plaques. Am J Pathol 147:668–677

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Zhang W, Geiman DE, Shields JM, Dang DT, Mahatan CS, Kaestner KH, Biggs JR, Kraft AS, Yang VW (2000) The gut-enriched Kruppel-like factor (Kruppel-like factor 4) mediates the transactivating effect of p53 on the p21WAF1/Cip1 promoter. J Biol Chem 275:18391–18398

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Chistiakov DA, Sobenin IA, Orekhov AN (2013) Regulatory T cells in atherosclerosis and strategies to induce the endogenous atheroprotective immune response. Immunol Lett 151:10–22

    Article  CAS  PubMed  Google Scholar 

  37. Klingenberg R, Gerdes N, Badeau RM, Gistera A, Strodthoff D, Ketelhuth DF, Lundberg AM, Rudling M, Nilsson SK, Olivecrona G, Zoller S, Lohmann C, Luscher TF, Jauhiainen M, Sparwasser T, Hansson GK (2013) Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. J Clin Invest 123:1323–1334

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Ammirati E, Cianflone D, Banfi M, Vecchio V, Palini A, De Metrio M, Marenzi G, Panciroli C, Tumminello G, Anzuini A, Palloshi A, Grigore L, Garlaschelli K, Tramontana S, Tavano D, Airoldi F, Manfredi AA, Catapano AL, Norata GD (2010) Circulating CD4+ CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis. Arterioscler Thromb Vasc Biol 30:1832–1841

    Article  CAS  PubMed  Google Scholar 

  39. Buckner JH (2010) Mechanisms of impaired regulation by CD4(+)CD25(+)FOXP3(+) regulatory T cells in human autoimmune diseases. Nat Rev Immunol 10:849–859

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Banerjee A, Vasanthakumar A, Grigoriadis G (2013) Modulating T regulatory cells in cancer: how close are we? Immunol Cell Biol 91:340–349

    Article  CAS  PubMed  Google Scholar 

  41. Facciabene A, Motz GT, Coukos G (2012) T-regulatory cells: key players in tumor immune escape and angiogenesis. Cancer Res 72:2162–2171

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Ramos KS, Partridge CR (2005) Atherosclerosis and cancer: flip sides of the neoplastic response in mammalian cells? Cardiovasc Toxicol 5:245–255

    Article  CAS  PubMed  Google Scholar 

  43. Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS (2001) Atherosclerosis: a cancer of the blood vessels? Am J Clin Pathol 116(Suppl):S97–S107

    PubMed  Google Scholar 

  44. Wolf AM, Wolf D, Steurer M, Gastl G, Gunsilius E, Grubeck-Loebenstein B (2003) Increase of regulatory T cells in the peripheral blood of cancer patients. Clin Cancer Res 9:606–612

    PubMed  Google Scholar 

  45. Caligiuri G, Nicoletti A (2010) Tregs and human atherothrombotic diseases: toward a clinical application? Arterioscler Thromb Vasc Biol 30:1679–1681

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Ha TY (2011) The role of miRNAs in regulatory T cells and in the immune response. Immune Netw 11:11–41

    Google Scholar 

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Acknowledgments

We would like to acknowledge Dr. Anoop Kumar for carrying out immunophenotyping analysis. We also thank W. E. Lowry and K. Plath for the KLF4 expression plasmid and Ms. M. Arora for editing the manuscript, and assistance with KLF4 cloning. This work was supported by Indian Council of Medical Research (ICMR), New Delhi, India.

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None declared.

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Authors and Affiliations

  1. Departments of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Mansi Arora & Deepak Kaul

  2. Department of Cardiology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Yash Paul Sharma

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  1. Mansi Arora
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  2. Deepak Kaul
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Correspondence to Deepak Kaul.

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Arora, M., Kaul, D. & Sharma, Y.P. Human coronary heart disease: importance of blood cellular miR-2909 RNomics. Mol Cell Biochem 392, 49–63 (2014). https://doi.org/10.1007/s11010-014-2017-3

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  • DOI: https://doi.org/10.1007/s11010-014-2017-3

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