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Critical Care

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Open Access 01-12-2015 | Research

Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study

Authors: Andrew J. Goodwin, Changrun Guo, James A. Cook, Bethany Wolf, Perry V. Halushka, Hongkuan Fan

Published in: Critical Care | Issue 1/2015

Abstract

Background

Endothelial dysfunction plays a critical role in the development of sepsis-related organ failure; however, the mechanisms that govern its development are not fully understood. Endothelial progenitor cells (EPCs) reduce vascular leak and organ failure in experimental sepsis while modulating plasma expression of microRNA (miRNA). MicroRNAs are small, noncoding segments of RNA that regulate gene expression and are known to modulate endothelial cell function and inflammatory signaling pathways. We hypothesized that miRNA may play an etiologic role in the endothelial dysfunction of sepsis and that their extracellular expression levels would be altered in those with shock.

Methods

Thirteen miRNAs were identified by literature search and analysis of the contents of human EPC-derived exosomes using real-time PCR. Plasma samples were obtained from patients within 24 hours of their admission to ICUs with severe sepsis (n = 62) and from healthy controls (n = 32) and real-time PCR was used to measure the expression of the candidate miRNAs. The Wilcoxon rank sum test was used to compare expression levels of the 13 candidate miRNAs in septic patients with (n = 29) and without (n = 33) shock while logistic regression was used to determine the area under the curve for associations between miRNA expression and shock. Bioinformatic analyses using miRNA databases were performed to identify pathways and gene targets of differentially expressed miRNA with potential relevance to sepsis-related shock.

Results

MiRNA-34a expression was significantly increased in the group who developed shock (p = 0.03) while miR-15a and miR-27a expressions were significantly decreased in this group (p = 0.006 and 0.03, respectively). The combined expression of these three miRNAs predicted shock with an area under the curve of 0.78 (95 % CI 0.66–0.90). In silico analyses predict that these three miRNAs regulate genes involved in endothelial cell cycle, apoptosis, VEGF signaling, LPS-stimulated MAPK signaling, and nuclear factor kappa B signaling.

Conclusions

The plasma levels of miRNA are altered in patients with severe sepsis complicated by shock and may offer prognostic value as well as insights into the mechanisms of endothelial dysfunction in sepsis.

Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992;101:1644–55.PubMed

Angus DC, van der Poll T. Severe sepsis and septic shock. N Engl J Med. 2013;369:2063.PubMed

Aird WC. The role of the endothelium in severe sepsis and multiple organ dysfunction syndrome. Blood. 2003;101:3765–77.PubMed

Faure E, Thomas L, Xu H, Medvedev A, Equils O, Arditi M. Bacterial lipopolysaccharide and IFN-gamma induce Toll-like receptor 2 and Toll-like receptor 4 expression in human endothelial cells: role of NF-kappa B activation. J Immunol. 2001;166:2018–24.PubMed

Henneke P, Golenbock DT. Innate immune recognition of lipopolysaccharide by endothelial cells. Crit Care Med. 2002;30(5 Suppl):S207–13.PubMed

Zhang FX, Kirschning CJ, Mancinelli R, Xu XP, Jin Y, Faure E, et al. Bacterial lipopolysaccharide activates nuclear factor-kappaB through interleukin-1 signaling mediators in cultured human dermal endothelial cells and mononuclear phagocytes. J Biol Chem. 1999;274:7611–4.PubMed

Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.PubMed

Lee RC, Ambros V. An extensive class of small RNAs in Caenorhabditis elegans. Science. 2001;294:862–4.PubMed

Lagos-Quintana M, Rauhut R, Lendeckel W, Tuschl T. Identification of novel genes coding for small expressed RNAs. Science. 2001;294:853–8.PubMed

10.

Valadi H, Ekstrom K, Bossios A, Sjostrand M, Lee JJ, Lotvall JO. Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells. Nat Cell Biol. 2007;9:654–9.PubMed

11.

Zernecke A, Bidzhekov K, Noels H, Shagdarsuren E, Gan L, Denecke B, et al. Delivery of microRNA-126 by apoptotic bodies induces CXCL12-dependent vascular protection. Sci Signal. 2009;2:ra81.PubMed

12.

Hergenreider E, Heydt S, Treguer K, Boettger T, Horrevoets AJ, Zeiher AM, et al. Atheroprotective communication between endothelial cells and smooth muscle cells through miRNAs. Nat Cell Biol. 2012;14:249–56.PubMed

13.

Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.PubMed

14.

Fan H, Goodwin AJ, Chang E, Zingarelli B, Borg K, Guan S, et al. Endothelial progenitor cells and a stromal cell-derived factor-1alpha analogue synergistically improve survival in sepsis. Am J Respir Crit Care Med. 2014;189:1509–19.PubMedPubMedCentral

15.

Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, et al. miR-126 regulates angiogenic signaling and vascular integrity. Dev Cell. 2008;15:272–84.PubMedPubMedCentral

16.

Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, et al. The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis. Dev Cell. 2008;15:261–71.PubMedPubMedCentral

17.

Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008;105:1516–21.PubMedPubMedCentral

18.

Wang X, Wang X, Liu X, Wang X, Xu J, Hou S, et al. miR-15a/16 are upreuglated in the serum of neonatal sepsis patients and inhibit the LPS-induced inflammatory pathway. Int J Clin Exp Med. 2015;8:5683–90.PubMedPubMedCentral

19.

Wang H, Zhang P, Chen W, Feng D, Jia Y, Xie LX. Evidence for serum miR-15a and miR-16 levels as biomarkers that distinguish sepsis from systemic inflammatory response syndrome in human subjects. Clin Chem Lab Med. 2012;50:1423–8.PubMed

20.

Acosta-Herrera M, Lorenzo-Diaz F, Pino-Yanes M, Corrales A, Valladares F, Klassert TE, et al. Lung transcriptomics during protective ventilatory support in sepsis-induced acute lung injury. PLoS One. 2015;10:e0132296.PubMedPubMedCentral

21.

Wang Z, Ruan Z, Mao Y, Dong W, Zhang Y, Yin N, et al. miR-27a is up regulated and promotes inflammatory response in sepsis. Cell Immunol. 2014;290:190–5.PubMed

22.

Roderburg C, Luedde M, Vargas Cardenas D, Vucur M, Scholten D, Frey N, et al. Circulating microRNA-150 serum levels predict survival in patients with critical illness and sepsis. PLoS One. 2013;8, e54612.PubMedPubMedCentral

23.

Ma Y, Vilanova D, Atalar K, Delfour O, Edgeworth J, Ostermann M, et al. Genome-wide sequencing of cellular microRNAs identifies a combinatorial expression signature diagnostic of sepsis. PLoS One. 2013;8:e75918.PubMedPubMedCentral

24.

Wang JF, Yu ML, Yu G, Bian JJ, Deng XM, Wan XJ, et al. Serum miR-146a and miR-223 as potential new biomarkers for sepsis. Biochem Biophys Res Commun. 2010;394:184–8.PubMed

25.

Wang HJ, Zhang PJ, Chen WJ, Feng D, Jia YH, Xie LX. Four serum microRNAs identified as diagnostic biomarkers of sepsis. J Trauma Acute Care Surg. 2012;73:850–4.PubMed

26.

Sun X, Icli B, Wara AK, Belkin N, He S, Kobzik L, et al. MicroRNA-181b regulates NF-kappaB-mediated vascular inflammation. J Clin Invest. 2012;122:1973–90.PubMedPubMedCentral

27.

Tili E, Michaille JJ, Cimino A, Costinean S, Dumitru CD, Adair B, et al. Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-alpha stimulation and their possible roles in regulating the response to endotoxin shock. J Immunol. 2007;179:5082–9.PubMed

28.

Taganov KD, Boldin MP, Chang KJ, Baltimore D. NF-kappaB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc Natl Acad Sci U S A. 2006;103:12481–6.PubMedPubMedCentral

29.

Song L, Lin C, Gong H, Wang C, Liu L, Wu J, et al. miR-486 sustains NF-kappaB activity by disrupting multiple NF-kappaB-negative feedback loops. Cell Res. 2013;23:274–89.PubMed

30.

McClure C, Brudecki L, Ferguson DA, Yao ZQ, Moorman JP, McCall CE, et al. MicroRNA 21 (miR-21) and miR-181b couple with NFI-A to generate myeloid-derived suppressor cells and promote immunosuppression in late sepsis. Infect Immun. 2014;82:3816–25.PubMedPubMedCentral

31.

Barnett RE, Conklin DJ, Ryan L, Keskey RC, Ramjee V, Sepulveda EA, et al. Anti-inflammatory effects of miR-21 in the macrophage response to peritonitis. J Leukoc Biol. 2015;17:1188–99.

32.

Force ADT, Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, et al. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307:2526–33.

33.

Medina RJ, O'Neill CL, O'Doherty TM, Wilson SEJ, Stitt AW. Endothelial Progenitors as Tools to Study Vascular Disease. Stem Cells Int. 2012;2012:346–735.

34.

TargetScanHuman: Prediction of microRNA targets. Available from: http://www.targetscan.org/. Accessed 16 July 2015

35.

microRNA.org - Targets and Expression. Available from: http://www.microrna.org/microrna/home.do. Accessed 16 July 2015.

36.

Miller TE, Ghoshal K, Ramaswamy B, Roy S, Datta J, Shapiro CL, et al. MicroRNA-221/222 confers tamoxifen resistance in breast cancer by targeting p27Kip1. J Biol Chem. 2008;283:29897–903.PubMedPubMedCentral

37.

Takagi T, Naito Y, Mizushima K, Hirata I, Yagi N, Tomatsuri N, et al. Increased expression of microRNA in the inflamed colonic mucosa of patients with active ulcerative colitis. J Gastroenterol Hepatol. 2010;25 Suppl 1:S129–33.PubMed

38.

Thery C, Ostrowski M, Segura E. Membrane vesicles as conveyors of immune responses. Nat Rev Immunol. 2009;9:581–93.PubMed

39.

Arroyo JD, Chevillet JR, Kroh EM, Ruf IK, Pritchard CC, Gibson DF, et al. Argonaute2 complexes carry a population of circulating microRNAs independent of vesicles in human plasma. Proc Natl Acad Sci U S A. 2011;108:5003–8.PubMedPubMedCentral

40.

Vickers KC, Palmisano BT, Shoucri BM, Shamburek RD, Remaley AT. MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins. Nat Cell Biol. 2011;13:423–33.PubMedPubMedCentral

41.

Gavard J, Gutkind JS. VEGF controls endothelial-cell permeability by promoting the beta-arrestin-dependent endocytosis of VE-cadherin. Nat Cell Biol. 2006;8:1223–34.PubMed

42.

van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock. 2005;23:35–8.PubMed

43.

Pickkers P, Sprong T, Eijk L, Hoeven H, Smits P, Deuren M. Vascular endothelial growth factor is increased during the first 48 hours of human septic shock and correlates with vascular permeability. Shock. 2005;24:508–12.PubMed

44.

Gao L, Grant A, Halder I, Brower R, Sevransky J, Maloney JP, et al. Novel polymorphisms in the myosin light chain kinase gene confer risk for acute lung injury. Am J Respir Cell Mol Biol. 2006;34:487–95.PubMedPubMedCentral

45.

Ackermann EJ, Taylor JK, Narayana R, Bennett CF. The role of antiapoptotic Bcl-2 family members in endothelial apoptosis elucidated with antisense oligonucleotides. J Biol Chem. 1999;274:11245–52.PubMed

46.

Potente M, Dimmeler S. Emerging roles of SIRT1 in vascular endothelial homeostasis. Cell Cycle. 2008;7:2117–22.PubMed

47.

Pan Y, Liang H, Liu H, Li D, Chen X, Li L, et al. Platelet-secreted microRNA-223 promotes endothelial cell apoptosis induced by advanced glycation end products via targeting the insulin-like growth factor 1 receptor. J Immunol. 2014;192:437–46.PubMed

48.

Pritchard CC, Kroh E, Wood B, Arroyo JD, Dougherty KJ, Miyaji MM, et al. Blood cell origin of circulating microRNAs: a cautionary note for cancer biomarker studies. Cancer Prev Res (Phila). 2012;5:492–7.

49.

Guduric-Fuchs J, O'Connor A, Camp B, O'Neill CL, Medina RJ, Simpson DA. Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types. BMC Genomics. 2012;13:357.PubMedPubMedCentral

50.

Pigati L, Yaddanapudi SC, Iyengar R, Kim DJ, Hearn SA, Danforth D, et al. Selective release of microRNA species from normal and malignant mammary epithelial cells. PLoS One. 2010;5:e13515.PubMedPubMedCentral

51.

Yin KJ, Olsen K, Hamblin M, Zhang J, Schwendeman SP, Chen YE. Vascular endothelial cell-specific microRNA-15a inhibits angiogenesis in hindlimb ischemia. J Biol Chem. 2012;287:27055–64.PubMedPubMedCentral

52.

Goretti E, Rolland-Turner M, Leonard F, Zhang L, Wagner DR, Devaux Y. MicroRNA-16 affects key functions of human endothelial progenitor cells. J Leukoc Biol. 2013;93:645–55.PubMed

53.

Ito T, Yagi S, Yamakuchi M. MicroRNA-34a regulation of endothelial senescence. Biochem Biophys Res Commun. 2010;398:735–40.PubMed

Title: Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study
Authors: Andrew J. Goodwin
Changrun Guo
James A. Cook
Bethany Wolf
Perry V. Halushka
Hongkuan Fan
Publication date: 01-12-2015
Publisher: BioMed Central
Published in: Critical Care / Issue 1/2015
Electronic ISSN: 1364-8535
DOI: https://doi.org/10.1186/s13054-015-1162-8

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Plasma levels of microRNA are altered with the development of shock in human sepsis: an observational study

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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