Open access

Abstract

Worldwide, cardiovascular diseases (CVDs) represent one of the main causes of morbidity and mortality, and acute coronary syndromes are responsible for a large number of sudden cardiac deaths. One of the main challenges that still exist in this area is represented by the early detection and targeted monitoring of the pathophysiology involved in CVDs. During the last couple of years, researchers have highlighted the importance of molecular and epigenetic mechanisms involved in the initiation and augmentation of CVDs, culminating in their most severe form represented by acute myocardial infarction. One of the most studied molecular factors involved in this type of pathology is represented by nuclear transcription factor kappa B (NF-κB), as well as the involvement of microRNAs (miRNAs). It has been suggested that miRNAs can also be involved in the complex process of atheromatous plaque vulnerabilization that leads to an acute cardiac event. In this review paper, we describe the most important molecular mechanisms involved in the pathogenesis of CVDs and atheromatous plaque progression and vulnerabilization, which include molecular mechanisms dependent on NF-κB. For this paper, we used international databases (PubMed and Scopus). The keywords used for the search were “miRNAs biomarkers”, “miRNAs in cardiovascular disease”, “NF-κB in cardiovascular disease”, “molecular mechanism in cardiovascular disease”, and “myocardial NF-κB mechanisms”. Numerous molecular reactions that have NF-κB as a trigger are involved in the pathogenesis of CVDs. Moreover, miRNAs play an important role in initiating and aggravating certain segments of CVDs. Therefore, miRNAs can be used as biomarkers for early evaluation of CVDs. Furthermore, in the future, miRNAs could be used as a targeted molecular therapy in order to block certain mechanisms responsible for inducing CVDs and leading to acute cardiovascular events.

1. Mitropoulos FA, Odim J, Marelli D, et al. Outcome of hearts with cold ischemic time greater than 300 minutes. A casematched study. Eur J Cardiothorac Surg. 2005;28:143-148. doi: 10.1016/j.ejcts.2005.01.067.

2. Tonkin AM, Blankenberg S, Kirby A, et al. Biomarkers in stable coronary heart disease, their modulation and cardiovascular risk: The LIPID biomarker study. Int J Cardiol. 2015;201:499-507. doi: 10.1016/j.ijcard.2015.07.080.

3. Vella RK, Pullen C, Coulson FR, Fenning AS. Resveratrol Prevents Cardiovascular Complications in the SHR/STZ Rat by Reductions in Oxidative Stress and Inflammation. Biomed Res Int. 2015;2015:918123. doi: 10.1155/2015/918123.

4. Melania L, Alexandru B, Rogobete F, et al. The Use of Redox Expression and Associated Molecular Damage to Evaluate the Inflammatory Response in Critically Ill Patient with Severe Burn. Biochem Genet. 2016;54:753-768. doi: 10.1007/s10528-016-9763-8

5. Rogobete AF, Sandesc D, Papurica M, et al. The influence of metabolic imbalances and oxidative stress on the outcome of critically ill polytrauma patients: a review. Burn Trauma. 2017;5:8. doi: 10.1186/s41038-017-0073-0.

6. Yang Y, Lv J, Jiang S, et al. The emerging role of Toll-like receptor 4 in myocardial inflammation. Cell Death Dis. 2016;7:e2234. doi: 10.1038/cddis.2016.140.

7. Weiss JBW, Eisenhardt SU, Stark GB, Bode C, Moser M, Grundmann S. MicroRNAs in ischemia-reperfusion injury. Am J Cardiovasc Dis. 2012;2:237-247.

8. Mansour Z, Charles AL, Kindo M, et al. Remote effects of lower limb ischemia-reperfusion: Impaired lung, unchanged liver, and stimulated kidney oxidative capacities. Biomed Res Int. 2014;2014:392390. doi: 10.1155/2014/392390.

9. David VL, Ercisli MF, Rogobete AF, et al. Early Prediction of Sepsis Incidence in Critically Ill Patients Using Specific Genetic Polymorphisms. Biochem Genet. 2017;55:193-203. doi: 10.1007/s10528-016-9785-2.

10. Kloppenborg RP, Nederkoorn PJ, van der Graaf Y, Geerlings MI. Homocysteine and cerebral small vessel disease in patients with symptomatic atherosclerotic disease. The SMARTMR study. Atherosclerosis. 2011;216:461-466. doi: 10.1016/j.atherosclerosis.2011.02.027.

11. Bedreag OH, Rogobete AF, Sandesc D, et al. The Effects of Homocysteine Level in the Critically Ill Patient. A Review. Journal of Interdisciplinary Medicine. 2016;1:131-136. doi: 10.1515/jim-2016-0025.

12. Li H, Horke S, Förstermann U. Vascular oxidative stress, nitric oxide and atherosclerosis. Atherosclerosis. 2014;237:208-219. doi: 10.1016/j.atherosclerosis.2014.09.001.

13. Bedreag OH, Rogobete AF, Cradigati CA, et al. A novel evaluation of microvascular damage in critically ill polytrauma patients by using circulating microRNAs. Romanian Journal of Laboratory Medicine. 2016;24:21-30. doi: 10.1515/rrlm-2016-0015.

14. Gareus R, Kotsaki E, Xanthoulea S, et al. Article Endothelial Cell-Specific NF-k B Inhibition Protects Mice from Atherosclerosis. Cell Metab. 2008;8:372-383. doi: 10.1016/j.cmet.2008.08.016.

15. Papurica M, Rogobete AF, Sandesc D, et al. The Expression of Nuclear Transcription Factor Kappa B (NF-κB) in the Case of Critically Ill Polytrauma Patients with Sepsis and Its Interactions with microRNAs. Biochem Genet. 2016;54:337-347. doi: 10.1007/s10528-016-9727-z.

16. Bedreag OH, Rogobete AF, Sărăndan M, et al. Oxidative stress and antioxidant therapy in traumatic spinal cord injuries. Rom J Anaesth Intensive Care. 2014;21:123-129.

17. Bedreag OH, Rogobete AF, Sarandan M, et al. Oxidative stress in severe pulmonary trauma in critical ill patients. Antioxidant therapy in patients with multiple trauma – a review. Anaesthesiol Intensive Ther. 2015;47:351-359. doi: 10.5603/AIT.a2015.0030.

18. Bedreag OH, Sandesc D, Chiriac SD, et al. The Use of Circulating miRNAs as Biomarkers for Oxidative Stress in Critically Ill Polytrauma Patients. Clin Lab. 2016;62:263-274. doi: 10.7754/Clin.Lab.2015.150740.

19. Papurica M, Rogobete AF, Sandesc D, et al. Advances in biomarkers in critical ill polytrauma patients. Clin Lab. 2016;62:977-986. doi: 10.7754/Clin.Lab.2015.151103.

20. Horhat FG, Gundogdu F, David LV, et al. Early Evaluation and Monitoring of Critical Patients with Acute Respiratory Distress Syndrome (ARDS) Using Specific Genetic Polymorphisms. 2017;55:204-211. doi: 10.1007/s10528-016-9787-0.

21. Papurica M, Rogobete AF, Sandesc D, et al. Redox Changes Induced by General Anesthesia in Critically Ill Patients with Multiple Traumas. Mol Biol Int. 2015;2015:238586. doi: 10.1155/2015/238586.

22. Dumache R, Rogobete AF, Bedreag OH, et al. Use of miRNAs as Biomarkers in Sepsis. Anal Cell Pathol (Amst). 2015;2015:186716. doi: 10.1155/2015/186716.

23. Sandesc M, Rogobete AF, Bedreag OH, et al. Analysis of oxidative stress-related markers in critically ill polytrauma patients: An observational prospective single-center study. Bosn J Basic Med Sci. 2018;18:191-197. doi: 10.17305/bjbms.2018.2306.

24. Magenta A, Cencioni C, Fasanaro P, et al. miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition. Cell Death Differ. 2011;18:1628-1639. doi: 10.1038/cdd.2011.42.

25. Zaccagnini G, Martelli F, Fasanaro P, et al. p66 ShcA Modulates Tissue Response to Hindlimb Ischemia. Circulation. 2004;109:2917-2923. doi: 10.1161/01.CIR.0000129309.58874.0F.

26. Lin Y, Liu X, Cheng Y, et al. Involvement of MicroRNAs in Hydrogen Peroxide-mediated Gene Regulation and Cellular Injury Response in Vascular Smooth Muscle Cells. J Biol Chem. 2009;284:7903-7913. doi: 10.1074/jbc.M806920200.

27. Cybulsky MI, Iiyama K, Li H, et al. A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest. 2001;107:1209-1210. doi: 10.1172/JCI11871.

28. Lu J, Liu F, Liu D, et al. Amlodipine and atorvastatin improved hypertensive cardiac hypertrophy through regulation of receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B/osteoprotegerin system in spontaneous hypertension rats. Exp Biol Med. 2016;241:1237-1249. doi: 10.1177/1535370216630180.

29. Bendaya I, Riahi A, Kharat M, et al. STAT1 and STAT6 Act as Antagonistic Regulators of PPAR γ in Diabetic Patients with and without Cardiovascular Diseases. Clin Lab. 2018;64:287-294. doi: 10.7754/Clin.Lab.2017.171013.

30. Fehlmann T, Meese E, Keller A. Exploring ncRNAs in Alzheimer’s disease by miRMaster. Oncotarget. 2017;8:3771-3772. doi: 10.18632/oncotarget.14054.

31. Bedreag OH, Rogobete AF, Sandesc D, et al. Modulation of the Redox Expression and Inflammation Response in the Crtically Ill Polytrauma Patient with Thoracic Injury. Statistical Correlations between Antioxidant Therapy and Clinical Aspects. A Retrospective Single Center Study. Clin Lab. 2016;62:1747-1759. doi: 10.7754/Clin.Lab.2016.160206.

32. Bratu LM, Rogobete AF, Papurica M, et al. Literature Research Regarding miRNAs’ Expression in the Assessment and Evaluation of the Critically Ill Polytrauma Patient with Traumatic Brain and Spinal Cord Injury. Clin Lab. 2016;62:2019-2024. doi: 10.7754/Clin.Lab.2016.160327.

33. Dumache R, Ciocan V, Muresan C, Enache A. Molecular DNA Analysis in Forensic Identification. Clin Lab. 2016;62:245-248. doi: 10.7754/Clin.Lab.2015.150414.

34. Cannino G, Di Liegro CM, Rinaldi AM. Nuclear-mitochondrial interaction. Mitochondrion. 2007;7:359-366. doi: 10.1016/j.mito.2007.07.001.

35. Karginov FV, Conaco C, Xuan Z, et al. A biochemical approach to identifying microRNA targets. Proc Natl Acad Sci U S A. 2007;104:19291-19296. doi: 10.1073/pnas.0709971104.

36. Yang Z, Cappello T, Wang L. Emerging role of microRNAs in lipid metabolism. Acta Pharm Sin B. 2015;5:145-150. doi: 10.1016/j.apsb.2015.01.002.

37. Pirtea L, Grigoraş D, Matusz P, et al. Human Papilloma Virus Persistence after Cone Excision in Women with Cervical High Grade Squamous Intraepithelial Lesion: A Prospective Study. Can J Infect Dis Med Microbiol. 2016;2016:3076380. doi: 10.1155/2016/3076380.

38. Pirtea L, Grigoraş D, Matusz P, et al. Age and HPV type as risk factors for HPV persistence after loop excision in patients with high grade cervical lesions: an observational study. BMC Surg. 2016;16:1-7. doi: 10.1186/s12893-016-0185-7.

39. Pirtea L, Raica M, Cimpean AM (2012) Endothelial cell activation and proliferation in ovarian tumors: Two distinct steps as potential markers for antiangiogenic therapy response. Mol Med Rep. 2012;5:1181-1184. doi: 10.3892/mmr.2012.812.

40. Zhang X, Azhar G, Wei JY. The Expression of microRNA and microRNA Clusters in the Aging Heart. PLoS One. 2012;7:1-13. doi: 10.1371/journal.pone.0034688.

41. Dumache R, Ciocan V, Muresan C, et al. Circulating microRNAs as promising biomarkers in forensic body fluids identification. Clin Lab. 2015;61:1129-1135. doi: 10.7754/Clin.Lab.2015.150207.

42. Dumache R, Muresan C, Ciocan V, et al. Post-Mortem Identification of a Fire Carbonized Body by STR Genotyping. Clin Lab. 2016;62:2033-2037. doi: 10.7754/Clin.Lab.2016.160417.

43. Ticlea M, Melania L, Bodog F, Horea O. The Use of Exosomes as Biomarkers for Evaluating and Monitoring Critically Ill Polytrauma Patients with Sepsis. Biochem Genet. 2017;55:1-9. doi: 10.1007/s10528-016-9773-6.

44. Nitu R, Florin A, Gundogdu F, et al. microRNAs Expression as Novel Genetic Biomarker for Early Prediction and Continuous Monitoring in Pulmonary Cancer. Biochem Genet. 2017;55:281-290. doi: 10.1007/s10528-016-9789-y.

45. Rogobete AF, Bedreag OH, Popovici SE, et al. Detection of Myocardial Injury Using miRNAs Expression as Genetic Biomarkers in Acute Cardiac Care. Journal of Cardiovascular Emergencies. 2016;2:169-172. doi: 10.1515/jce-2016-0025.

46. Papurica M, Rogobete AF, Sandesc D, et al. Using the Expression of Damage-Associated Molecular Pattern (DAMP) for the Evaluation and Monitoring of the Critically Ill Polytrauma Patient. Clin Lab. 2016;62:1829-1840. doi: 10.7754/Clin.Lab.2016.160226.

47. Sandesc M, Dinu A, Rogobete AF, et al. Circulating microRNAs expressions as genetic biomarkers in pancreatic cancer patients continuous non-invasive monitoring. Clin Lab. 2017;63:1561-1566. doi: 10.7754/Clin.Lab.2017.170608.

48. Negoita SI, Sandesc D, Rogobete AF, et al (2017) MiRNAs expressions and interaction with biological systems in patients with Alzheimer’s disease. Using miRNAs as a diagnosis and prognosis biomarker. Clin Lab. 2017;63:1315-1321. doi: 10.7754/Clin.Lab.2017.170327.

49. Bratu LM, Rogobete AF, Papurica M, et al. Literature Research Regarding miRNAs’ Expression in the Assessment and Evaluation of the Critically Ill Polytrauma Patient with Traumatic Brain and Spinal Cord Injury. Clin Lab. 2016;62:2019-2024. doi: 10.7754/Clin.Lab.2016.160327.

50. Bedreag OH, Sandesc D, Chiriac SD, et al. The Use of Circulating miRNAs as Biomarkers for Oxidative Stress in Critically Ill Polytrauma Patients. Clin Lab. 2016;62:263-274.doi: 10.7754/Clin.Lab.2015.150740.

51. McCall CE, El Gazzar M, Liu T, Vachharajani V, Yoza B. Epigenetics, bioenergetics, and microRNA coordinate genespecific reprogramming during acute systemic inflammation. J Leukoc Biol. 2011;90:439-46. doi: 10.1189/jlb.0211075.

52. Olivieri F, Rippo MR, Prattichizzo F, et al. Toll like receptor signaling in “inflammaging”: microRNA as new players. Immun Ageing. 2013;10:11. doi: 10.1186/1742-4933-10-11.

53. Ucar A, Gupta SK, Fiedler J, et al. The miRNA-212/132 family regulates both cardiac hypertrophy and cardiomyocyte autophagy. Nat Commun. 2012;3:1078. doi: 10.1038/ncomms2090.

54. Long G, Wang F, Duan Q, et al. Human Circulating MicroRNA-1 and MicroRNA-126 as Potential Novel Indicators for Acute Myocardial Infarction. Int J Biol Sci. 2012;8:811-888. doi: 10.7150/ijbs.4439.

55. Greco S, Gorospe M, Martelli F. Noncoding RNA in age-related cardiovascular diseases. J Mol Cell Cardiol. 2015;83:142-155. doi: 10.1016/j.yjmcc.2015.01.011.

56. Fichtlscherer S, Rosa S De, Fox H, et al. Circulating MicroRNAs in Patients With Coronary Artery Disease. Circ Res. 2010;107:677-684. doi: 10.1161/CIRCRESAHA.109.215566.

57. Romaine SPR, Tomaszewski M, Condorelli G, Samani NJ. MicroRNAs in cardiovascular disease: An introduction for clinicians. Heart. 2015;101:921-928. doi: 10.1136/heartjnl-2013-305402.

58. Cheng Y, Tan N, Yang J, et al. A translational study of circulating cell-free microRNA-1 in acute myocardial infarction. 2010;95:87-95. doi: 10.1042/CS20090645.

59. Gidlöf O, Andersson P, Pals J Van Der, et al. Cardiospecific microRNA Plasma Levels Correlate with Troponin and Cardiac Function in Patients with ST Elevation Myocardial Infarction, Are Selectively Dependent on Renal Elimination, and Can Be Detected in Urine Samples. Cardiology. 2011;118:217-226. doi: 10.1159/000328869.

60. Wang R, Li N, Zhang Y, et al. Circulating MicroRNAs are Promising Novel Biomarkers of Acute Myocardial Infarction. Intern Med. 2011;50:1789-1795. doi: 10.2169/internalmedicine.50.5129.

61. Alessandra YD, Carena MC, Spazzafumo L, et al. Diagnostic Potential of Plasmatic MicroRNA Signatures in Stable and Unstable Angina. PLoS One. 2013;8:e80345. doi: 10.1371/journal.pone.0080345.

62. Hoekstra M, van der Lans CAC, Halvorsen B, et al. The peripheral blood mononuclear cell microRNA signature of coronary artery disease. Biochem Biophys Res Commun. 2010;394:792-797. doi: https://doi.org/10.1016/j.bbrc.2010.03.075.

63. Tijsen AJ, Creemers EE, Moerland PD, et al. MiR423-5p as a circulating biomarker for heart failure. Circ Res. 2010;106:1035-1039. doi: 10.1161/CIRCRESAHA.110.218297.

64. Caporali A, Meloni M, Vo C, et al. Deregulation of microRNA-503 Contributes to Diabetes Mellitus-Induced Impairment of Endothelial Function and Reparative Angiogenesis After Limb Ischemia. Circulation. 2011;123:282-291. doi: 10.1161/CIRCULATIONAHA.110.952325.

65. Liu C, Liu N, Cao B, et al. CircRNAs as Potential Biomarkers in Gastrointestinal Tract Tumors : Opportunities and Challenges. Clin Lab. 2018;64:141-145. doi: 10.7754/Clin.Lab.2017.170731.

66. Giden R, Gökdemir MT, Erel Ö, et al. The Relationship Between Serum Thiol Levels and Thiol/Disulfide Homeostasis with Head Trauma in Children. Clin Lab. 2018;64:163-168. doi: 10.7754/Clin.Lab.2017.170816.

67. Ma X, Buscaglia LEB, Barker JR, Li Y. MicroRNAs in NF-k B signaling. J Mol Cell Biol. 2011;3:159-166. doi: 10.1093/jmcb/mjr007.

68. Oeckinghaus A, Ghosh S. The NF-k B Family of Transcription Factors and Its Regulation. Cold Spring Harb Perspect Biol. 2009;1:a000034. doi: 10.1101/cshperspect.a000034.

69. Zhang H, Sun SC. NF‑κB in inflammation and renal diseases. Cell Biosci. 2015;5:63. doi: 10.1186/s13578-015-0056-4.

70. Kleniewska P, Piechota-polanczyk A, Michalski L, et al. Influence of Block of NF-Kappa B Signaling Pathway on Oxidative Stress in the Liver Homogenates. Oxid Med Cell Longev. 2013;2013:308358. doi: 10.1155/2013/308358.

71. Hajra L, Evans AI, Chen M, et al. The NF-κB signal transduction pathway in aortic endothelial cells is primed for activation in regions predisposed to atherosclerotic lesion formation. Proc Natl Acad Sci U S A. 2000;97:9052-9057.

72. Kanters E, Pasparakis M, Gijbels MJJ, et al. Inhibition of NF-κB activation in macrophages increases atherosclerosis in LDL receptor-deficient mice. J Clin Invest. 2003;112:1176-1185. doi: 10.1172/JCI18580.

73. Yurdagul A, Sulzmaier FJ, Chen XL, et al. Oxidized LDL induces FAK-dependent RSK signaling to drive NF-κB activation and VCAM-1 expression. J Cell Sci. 2016;129:1580-1591. doi: 10.1242/jcs.182097.

74. Meng Y, Chen C, Liu Y, et al. Angiotensin II Regulates Dendritic Cells through Activation of NF-κB/p65, ERK1/2 and STAT1 Pathways. Cell Physiol Biochem. 2017;42:1550-1558. doi: 10.1159/000479272.

75. Wang H, Wei Y, Zeng Y, et al. The association of polymorphisms of TLR4 and CD14 genes with susceptibility to sepsis in a Chinese population. BMC Med Genet. 2014;15:123. doi: 10.1186/s12881-014-0123-4.

76. Ye E, Steinle JJ. miR-146a Attenuates Inflammatory Pathways Mediated by TLR4/NF-κB and TNF-α to Protect Primary Human Retinal Microvascular Endothelial Cells Grown in High Glucose. Mediators of Inflammation. 2016;2016:3958453. https://doi.org/10.1155/2016/3958453.

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