Abstract
Endothelial cell dysfunction is a term which implies the dysregulation of normal endothelial cell functions, including impairment of the barrier functions, control of vascular tone, disturbance of proliferative and migratory capacity of endothelial cells, as well as control of leukocyte trafficking. Endothelial dysfunction is an early step in vascular inflammatory diseases such as atherosclerosis, diabetic vascular complications, sepsis-induced or severe virus infection-induced organ injuries. The expressions of inflammatory cytokines and vascular adhesion molecules induced by various stimuli, such as modified lipids, smoking, advanced glycation end products and bacteria toxin, significantly contribute to the development of endothelial dysfunction. The transcriptional regulation of inflammatory cytokines and vascular adhesion molecules has been well-studied. However, the regulation of those gene expressions at post-transcriptional level is emerging. RNA-binding proteins have emerged as critical regulators of gene expression acting predominantly at the post-transcriptional level in microRNA-dependent or independent manners. This review summarizes the latest insights into the roles of RNA-binding proteins in controlling vascular endothelial cell functions and their contribution to the pathogenesis of vascular inflammatory diseases.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Rajendran P, Rengarajan T, Thangavel J, Nishigaki Y, Sakthisekaran D, Sethi G, Nishigaki I. The vascular endothelium and human diseases. Int J Biol Sci, 2013, 9: 1057–1069
Cheng Z, Yang X, Wang H. Hyperhomocysteinemia and Endothelial Dysfunction. CurrHypertens Rev, 2009, 5: 158–165
Herrera MD, Mingorance C, Rodríguez-Rodríguez R, Alvarez de Sotomayor M. Endothelial dysfunction and aging: an update. Ageing Res Rev, 2010, 9: 142–152
Winn RK, Harlan JM. The role of endothelial cell apoptosis in inflammatory and immune diseases. J ThrombHaemost, 2005, 3: 1815–1824
Sahni SK. Endothelial cell infection and hemostasis. Thromb Res, 2007, 119: 531–549
Menghini R, Casagrande V, Federici M. microRNAs in endothelial senescence and atherosclerosis. J CardiovascTransl Res, 2013, 6: 924–930
Anderson P. Post-transcriptional regulons coordinate the initiation and resolution of inflammation. Nat Rev Immunol, 2010, 10: 24–35
Anderson P. Post-transcriptional control of cytokine production. Nat Immunol, 2009, 9: 353–359
Small EM, Olson EN. Pervasive roles of microRNAs in cardiovascular biology. Nature, 2011, 469: 336–342
Ambros V. The functions of animal microRNAs. Nature, 2004, 431: 350–355
Cullen BR. Viral and cellular messenger RNA targets of viral microRNAs. Nature, 2009, 457: 421–425
Condorelli G, Latronico MV, Cavarretta E. microRNAs in cardiovascular diseases: current knowledge and the road ahead. J Am CollCardiol, 2014, pii: S0735-1097(14)01108-5
Chamorro-Jorganes A, Araldi E, Suárez Y. microRNAs as pharmacological targets in endothelial cell function and dysfunction. Pharmacol Res, 2013, 75: 15–27
Madrigal-Matute J, Rotllan N, Aranda JF, Fernández-Hernando C. microRNAs and atherosclerosis. Curr Atheroscler Rep, 2013, 15: 322
Santoro MM, Nicoli S. miRNAs in endothelial cell signaling: the endomiRNAs. Exp Cell Res, 2013, 319: 1324–1330
Gresele P, Falcinelli E, Sebastiano M, Baldelli F. Endothelial and platelet function alterations in HIV-infected patients. Thromb Res, 2012, 129: 301–308
Charreau B. Molecular regulation of endothelial cell activation: novel mechanisms and emerging targets. Curr Opin Organ Transplant, 2011, 16: 207–213
Lusis AJ. Atherosclerosis. Nature, 2000, 407: 233–241
Libby P. Inflammation in atherosclerosis. Nature, 2002, 420: 868–874
Polovina MM, Potpara TS. Endothelial dysfunction in metabolic and vascular disorders. Postgrad Med, 2014, 126: 38–53
Gutiérrez E, Flammer AJ, Lerman LO, Elízaga J, Lerman A, Fernández-Avilés F. Endothelial dysfunction over the course of coronary artery disease. Eur Heart J, 2013, 34: 3175–3181
Sena CM, Pereira AM, Seiça R. Endothelial dysfunction — a major mediator of diabetic vascular disease. Biochim Biophys Acta, 2013, 1832: 2216–2231
Barton M. Prevention and endothelial therapy of coronary artery disease. Curr Opin Pharmacol, 2013, 13: 226–241
Mauricio MD, Aldasoro M, Ortega J, Vila JM. Endothelial dysfunction in morbid obesity. Curr Pharm Des, 2013, 19: 5718–5729
Picchi A, Gao X, Belmadani S, Potter BJ, Focardi M, Chilian WM, Zhang C. Tumor necrosis factor-alpha induces endothelial dysfunction in the prediabetic metabolic syndrome. Circ Res, 2006, 99: 69–77
Imamura A, Takahashi R, Murakami R, Kataoka H, Cheng XW, Numaguchi Y, Murohara T, Okumura K. The effects of endothelial nitric oxide synthase gene polymorphisms on endothelial function and metabolic risk factors in healthy subjects: the significance of plasma adiponectin levels. Eur J Endocrinol, 2008, 158: 189–195
Deutschman CS, Tracey KJ. Sepsis: current dogma and new perspectives. Immunity, 2014, 40: 463–475
De Backer D, Orbegozo Cortes D, Donadello K, Vincent JL. Pathophysiology of microcirculatory dysfunction and the pathogenesis of septic shock. Virulence, 2014, 5: 73–79
Müller MM, Griesmacher A. Markers of endothelial dysfunction. ClinChem Lab Med, 2000, 38: 77–85
Page AV, Liles WC. Biomarkers of endothelial activation/dysfunction in infectious diseases. Virulence, 2013, 4: 507–516
Lee WL, Liles WC. Endothelial activation, dysfunction and permeability during severe infections. Curr Opin Hematol, 2011, 18: 191–196
Armstrong SM, Darwish I, Lee WL. Endothelial activation and dysfunction in the pathogenesis of influenza A virus infection. Virulence, 2013, 4: 537–542
Gresele P, Falcinelli E, Sebastiano M, Baldelli F. Endothelial and platelet function alterations in HIV-infected patients. Thromb Res, 2012, 129: 301–308
Charreau B. Molecular regulation of endothelial cell activation: novel mechanisms and emerging targets. Curr Opin Organ Transplant, 2011, 16: 207–213
Liu P, Woda M, Ennis FA, Libraty DH. Dengue virus infection differentially regulates endothelial barrier function over time through type I interferon effects. J Infect Dis, 2009, 200: 191–201
Rajapakse S. Dengue shock. J Emerg Trauma Shock, 2011, 4: 120–127
Whelan JT, Hollis SE, Cha DS, Asch AS, Lee MH. Post-transcriptional regulation of the Ras-ERK/MAPK signaling pathway. J Cell Physiol, 2012, 227: 1235–1241
Glisovic T, Bachorik JL, Yong J, Dreyfuss G. RNA-binding proteins and post-transcriptional gene regulation. FEBS Lett, 2008, 582: 1977–1986
Brooks SA, Blackshear PJ. Tristetraprolin (TTP): interactions with mRNA and proteins, and current thoughts on mechanisms of action. Biochim Biophys Acta, 2013, 1829: 666–679
Ciais D, Cherradi N, Feige JJ. Multiple functions of tristetraprolin/TIS11 RNA-binding proteins in the regulation of mRNA biogenesis and degradation. Cell Mol Life Sci, 2013, 70: 2031–2044
Carrick DM, Lai WS, Blackshear PJ. The tandem CCCH zinc finger protein tristetraprolin and its relevance to cytokine mRNA turnover and arthritis. Arthritis Res Ther, 2004, 6: 248–264
Carballo E, Lai WS, Blackshear PJ. Evidence that tristetraprolin is a physiological regulator of granulocyte-macrophage colony-stimulating factor messenger RNA deadenylation and stability. Blood, 2000, 95: 1891–1899
Ogilvie RL, Abelson M, Hau HH, Vlasova I, Blackshear PJ, Bohjanen PR. Tristetraprolin down-regulates IL-2 gene expression through AU-rich element-mediated mRNA decay. J Immunol, 2005, 174: 953–961
Zhao W, Liu M, D’Silva NJ, Kirkwood KL. Tristetraprolin regulates interleukin-6 expression through p38 MAPK-dependent affinity changes with mRNA 3′ untranslated region. J Interferon Cytokine Res, 2011, 31: 629–637
Fechir M, Linker K, Pautz A, Hubrich T, Förstermann U, Rodriguez-Pascual F, Kleinert H. Tristetraprolin regulates the expression of the human inducible nitric-oxide synthase gene. Mol Pharmacol, 2005, 67: 2148–2161
Datta S, Biswas R, Novotny M, Pavicic PG Jr, Herjan T, Mandal P, Hamilton TA. Tristetraprolin regulates CXCL1 (KC) mRNA stability. J Immunol, 2008, 180: 2545–2552
Stoecklin G, Tenenbaum SA, Mayo T, Chittur SV, George AD, Baroni TE, Blackshear PJ, Anderson P. Genome-wide analysis identifies interleukin-10 mRNA as target of tristetraprolin. J Biol Chem, 2008, 283: 11689–11699
Taylor GA, Carballo E, Lee DM, Lai WS, Thompson MJ, Patel DD, Schenkman DI, Gilkeson GS, Broxmeyer HE, Haynes BF, Blackshear PJ. A pathogenetic role for TNFalpha in the syndrome of cachexia, arthritis, and autoimmunity resulting from tristetraprolin (TTP) deficiency. Immunity, 1996, 4: 445–454
Carballo E, Lai WS, Blackshear PJ. Feedback inhibition of macrophage tumor necrosis factor-alpha production by tristetraprolin. Science, 1998, 281: 1001–1005
Blackshear PJ, Perera L. Phylogenetic Distribution and evolution of the linked RNA-binding and NOT1-binding domains in the tristetraprolin family of tandem CCCH zinc finger proteins. J Interferon Cytokine Res, 2014, 34: 297–306
Lai WS, Perera L, Hicks SN, Blackshear PJ. Mutational and structural analysis of the tandem zinc finger domain of tristetraprolin. J Biol Chem, 2014, 289: 565–580
Fabian MR, Frank F, Rouya C, Siddiqui N, Lai WS, Karetnikov A, Blackshear PJ, Nagar B, Sonenberg N. Structural basis for the recruitment of the human CCR4-NOT deadenylase complex by tristetraprolin. Nat StructMol Biol, 2013, 20: 735–739
Jing Q, Huang S, Guth S, Zarubin T, Motoyama A, Chen J, Di Padova F, Lin SC, Gram H, Han J. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell, 2005, 120: 623–634
Bollmann F, Wu Z, Oelze M, Siuda D, Xia N, Henke J, Daiber A, Li H, Stumpo DJ, Blackshear PJ, Kleinert H, Pautz A. Endothelial dysfunction in tristetraprolin-deficient mice is not caused by enhanced TNF-α expression. J Biol Chem, 2014, 289: 15653–15665
Zhang H, Taylor WR, Joseph G, Caracciolo V, Gonzales DM, Sidell N, Seli E, Blackshear PJ, Kallen CB. mRNA-binding protein ZFP36 is expressed in atherosclerotic lesions and reduces inflammation in aortic endothelial cells. Arterioscler Thromb Vasc Biol, 2013, 33: 1212–1220
Dai XY, Cai Y, Sun W, Ding Y, Wang W, Kong W, Tang C, Zhu Y, Xu MJ, Wang X. Intermedin inhibits macrophage foam-cell formation via tristetraprolin-mediated decay of CD36 mRNA. Cardiovasc Res, 2014, 101: 297–305
Chamboredon S, Ciais D, Desroches-Castan A, Savi P, Bono F, Feige JJ, Cherradi N. Hypoxia-inducible factor-1α mRNA: a new target for destabilization by tristetraprolin in endothelial cells. MolBiol Cell, 2011, 22: 3366–3378
Qiu LQ, Stumpo DJ, Blackshear PJ. Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. J Immunol, 2012, 188: 5150–5159
Chang SH, Hla T. Post-transcriptional gene regulation by HuR and microRNAs in angiogenesis. Curr Opin Hematol, 2014, 21: 235–240
Pullmann R Jr, Rabb H. HuR and other turnover- and translation-regulatory RNA-binding proteins: implications for the kidney. Am J Physiol Renal Physiol, 2014, 306: F569–576
Ceolotto G, de Kreutzenberg SV, Cattelan A, Fabricio AS, Squarcina E, Gion M, Semplicini A, Fadini GP, Avogaro A. Sirtuin 1 stabilization by HuR represses TNF-α and glucose induced E-selectin release and endothelial cell adhesiveness in vitro. Relevance to human metabolic syndrome. Clin Sci (Lond), 2014, 127: 449–461
Kurosu T, Ohga N, Hida Y, Maishi N, Akiyama K, Kakuguchi W, Kuroshima T, Kondo M, Akino T, Totsuka Y, Shindoh M, Higashino F, Hida K. HuR keeps an angiogenic switch on by stabilising mRNA of VEGF and COX-2 in tumour endothelium. Br J Cancer, 2011, 104: 819–829
Lin FY, Chen YH, Lin YW, Tsai JS, Chen JW, Wang HJ, Chen YL, Li CY, Lin SJ. The role of human antigen R, an RNA-binding protein, in mediating the stabilization of toll-like receptor 4 mRNA induced by endotoxin: a novel mechanism involved in vascular inflammation. Arterioscler Thromb Vasc Biol, 2006, 26: 2622–2629
Shi JX, Su X, Xu J, Zhang WY, Shi Y. HuR post-transcriptionally regulates TNF-α-induced IL-6 expression in human pulmonary microvascular endothelial cells mainly via tristetraprolin. Respir Physiol Neurobiol, 2012, 181: 154–161
Tiedje C, Ronkina N, Tehrani M, Dhamija S, Laass K, Holtmann H, Kotlyarov A, Gaestel M. The p38/MK2-driven exchange between tristetraprolin and HuR regulates AU-rich element-dependent translation. PLoS Genet, 2012, 8: e1002977
Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI, Fish JE. microRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Mol Med, 2013, 5: 949–966
Zhang J, Modi Y, Yarovinsky T, Yu J, Collinge M, Kyriakides T, Zhu Y, Sessa WC, Pardi R, Bender JR. Macrophage β2 integrinmediated, HuR-dependent stabilization of angiogenic factorencoding mRNAs in inflammatory angiogenesis. Am J Pathol, 2012, 180: 1751–1760
Pullmann R Jr, Juhaszova M, López de Silanes I, Kawai T, Mazan-Mamczarz K, Halushka MK, Gorospe M. Enhanced proliferation of cultured human vascular smooth muscle cells linked to increased function of RNA-binding protein HuR. J Biol Chem, 2005, 280: 22819–22826
Uehata T, Akira S. mRNA degradation by the endoribonucleaseRegnase-1/ZC3H12a/MCPIP-1. Biochim Biophys Acta, 2013, 1829: 708–713
Jura J, Skalniak L, Koj A. Monocyte chemotactic protein-1-induced protein-1(MCPIP1) is a novel multifunctional modulator of inflammatory reactions. Biochim Biophys Acta, 2012, 1823: 1905–1913
Matsushita K, Takeuchi O, Standley DM, Kumagai Y, Kawagoe T, Miyake T, Satoh T, Kato H, Tsujimura T, Nakamura H, Akira S. Zc3h12a is an RNase essential for controlling immune responses by regulating mRNA decay. Nature, 2009, 458: 1185–1190
Liang J, Wang J, Azfer A, Song W, Tromp G, Kolattukudy PE, Fu M. A novel CCCH-zinc finger protein family regulates proinflammatory activation of macrophages. J Biol Chem, 2008, 283: 6337–6346
Liang J, Song W, Tromp G, Kolattukudy PE, Fu M. Genome-wide survey and expression profiling of CCCH-zinc finger family reveals a functional module inmacrophage activation. PLoS ONE, 2008, 3: e2880
Mizgalska D, Wegrzyn P, Murzyn K, Kasza A, Koj A, Jura J, Jarzab B, Jura J. Interleukin-1-inducible MCPIP protein has structural and functional properties of RNase and participates in degradation of IL-1beta mRNA. FEBS J, 2009, 276: 7386–7399
Li M, Cao W, Liu H, Zhang W, Liu X, Cai Z, Guo J, Wang X, Hui Z, Zhang H, Wang J, Wang L. MCPIP1 down-regulates IL-2 expression through an ARE-independent pathway. PLoS ONE, 2012, 7: e49841
Liang J, Saad Y, Lei T, Wang J, Qi D, Yang Q, Kolattukudy PE, Fu M. MCP-induced protein 1 deubiquitinates TRAF proteins and negatively regulates JNK and NF-kappaB signaling. J Exp Med, 2010, 207: 2959–2973
Miao R, Huang S, Zhou Z, Quinn T, Van Treeck B, Nayyar T, Dim D, Jiang Z, Papasian CJ, Eugene Chen Y, Liu G, Fu M. Targeted disruption of MCPIP1/Zc3h12a results in fatal inflammatory disease. Immunol Cell Biol, 2013, 91: 368–376
Qi Y, Liang J, She ZG, Cai Y, Wang J, Lei T, Stallcup WB, Fu M. MCP-induced protein 1 suppresses TNFalpha-induced VCAM-1 expression in human endothelial cells. FEBS Lett, 2010, 584: 3065–3072
Huang S, Miao R, Zhou Z, Wang T, Liu J, Liu G, Chen YE, Xin HB, Zhang J, Fu M. MCPIP1 negatively regulates toll-like receptor 4 signaling and protects mice from LPS-induced septic shock. Cell Signal, 2013, 25: 1228–1234
Liu L, Zhou Z, Huang S, Guo Y, Fan Y, Zhang J, Zhang J, Fu M, Chen YE. Zc3h12c inhibits vascular inflammation by repressing NF-κB activation and pro-inflammatory gene expression in endothelial cells. Biochem J, 2013, 451: 55–60
Xu J, Peng W, Sun Y, Wang X, Xu Y, Li X, Gao G, Rao Z. Structural study of MCPIP1 N-terminal conserved domain reveals a PIN-like RNase. Nucleic Acids Res, 2012, 40: 6957–6965
Qi D, Huang S, Miao R, She ZG, Quinn T, Chang Y, Liu J, Fan D, Chen YE, Fu M. Monocyte chemotactic protein-induced protein 1 (MCPIP1) suppresses stress granule formation and determines apoptosis under stress. J Biol Chem, 2011, 286: 41692–41700
Suzuki HI, Arase M, Matsuyama H, Choi YL, Ueno T, Mano H, Sugimoto K, Miyazono K. MCPIP1 ribonuclease antagonizes dicer and terminates microRNA biogenesis through precursor microRNA degradation. Mol Cell, 2011, 44: 424–436
Fan P, Chen Z, Tian P, Liu W, Jiao Y, Xue Y, Bhattacharya A, Wu J, Lu M, Guo Y, Cui Y, Gu W, Gu W, Yue J. miRNA biogenesis enzyme Drosha is required for vascular smooth muscle cell survival. PLoS ONE, 2013, 8: e60888
Chen Z, Wu J, Yang C, Fan P, Balazs L, Jiao Y, Lu M, Gu W, Li C, Pfeffer LM, Tigyi G, Yue J. DiGeorge syndrome critical region 8 (DGCR8) protein-mediated microRNA biogenesis is essential for vascular smooth muscle cell development in mice. J Biol Chem, 2012, 287: 19018–19028
Pan Y, Balazs L, Tigyi G, Yue J. Conditional deletion of Dicer in vascular smooth muscle cells leads to the developmental delay and embryonic mortality. Biochem Biophys Res Commun, 2011, 408: 369–374
Asai T, Suzuki Y, Matsushita S, Yonezawa S, Yokota J, Katanasaka Y, Ishida T, Dewa T, Kiwada H, Nango M, Oku N. Disappearance of the angiogenic potential of endothelial cells caused by Argonaute 2 knockdown. Biochem Biophys Res Commun, 2008, 368: 243–248
Pin AL, Houle F, Guillonneau M, Paquet ER, Simard MJ, Huot J. miR-20a represses endothelial cell migration by targeting MKK3 and inhibiting p38 MAP kinase activation in response to VEGF. Angiogenesis, 2012, 15: 593–608
Justice MJ, Hirschi KK. The role of quaking in mammalian embryonic development. AdvExp Med Biol, 2010, 693: 82–92
van der Veer EP, de Bruin RG, Kraaijeveld AO, de Vries MR, Bot I, Pera T, Segers FM, Trompet S, van Gils JM, Roeten MK, Beckers CM, van Santbrink PJ, Janssen A, van Solingen C, Swildens J, de Boer HC, Peters EA, Bijkerk R, Rousch M, Doop M, Kuiper J, Schalij MJ, van der Wal AC, Richard S, van Berkel TJ, Pickering JG, Hiemstra PS, Goumans MJ, Rabelink TJ, de Vries AA, Quax PH, Jukema JW, Biessen EA, van Zonneveld AJ. Quaking, an RNA-binding protein, is a critical regulator of vascular smooth muscle cell phenotype. Circ Res, 2013, 113: 1065–1075
Noveroske JK, Lai L, Gaussin V, Northrop JL, Nakamura H, Hirschi KK, Justice MJ. Quaking is essential for blood vessel development. Genesis, 2002, 32: 218–230
Tsukamoto Y, Matsuo N, Ozawa K, Hori O, Higashi T, Nishizaki J, Tohnai N, Nagata I, Kawano K, Yutani C, Hirota S, Kitamura Y, Stern DM, Ogawa S. Expression of a novel RNA-splicing factor, RA301/Tra2beta, in vascular lesions and its role in smooth muscle cell proliferation. Am J Pathol, 2001, 158: 1685–1694
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is published with open access at link.springer.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Xin, H., Deng, K. & Fu, M. Post-transcriptional gene regulation by RNA-binding proteins in vascular endothelial dysfunction. Sci. China Life Sci. 57, 836–844 (2014). https://doi.org/10.1007/s11427-014-4703-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-014-4703-5