Atorvastatin suppresses lipopolysaccharideinduced inflammation in human coronary artery endothelial cells
DOI:
https://doi.org/10.1590/s2175-979020200001181092Palavras-chave:
Atorvastatin, TLR4, Lipopolysaccharide, Endothelial cells, InflammationResumo
he present study was designed to examine the effects of atorvastatin on vascular inflammatory responses in human coronary artery endothelial cells(HCAECs), when challenged by lipopolysaccharide (LPS), a Toll-like receptor-4 (TLR4) ligand. HCAECs were pretreated with atorvastatin and induced by LPS. The expression of TLR4, interleukin -6(IL-6), monocyte chemoattractant protein 1(MCP-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecular-1(ICAM-1), nuclear factor-κB (NF-κB) and p38 mitogen activated protein kinase(p38 MAPK) were evaluated using Real-time polymerase chain reaction, cytokine ELISA assay and Western blotting. The results showed that pretreatment with atorvastatin down-regulated the expression of TLR4 in LPS-activated HCAECs. Atorvastatin also attenuated the LPS-induced expression of interleukin IL-6 and MCP-1, at both the transcription and translation level in HCAECs. LPS-induced endothelial cell adhesion molecules, ICAM-1 and VCAM-1 expression were also reduced by pretreatment with atorvastatin. Furthermore, atorvastatin efficiently suppressed LPS-induced phosphorylation of NF-κB and p38 MAPK in HCAECs. These findings show that atorvastatin suppresses endothelial cell inflammation, suggesting that atorvastatin may be suitable for development as a therapeutic agent for inflammatory cardiovascular disease.
Downloads
Referências
Abreu MT, Vora P, Faure E, Thomas LS, Arnold ET and Arditi M. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide. J Immunol. 2001;167(3):1609-16.
Akira S, Takeda K and Kaisho T. Toll-like receptors: critical proteins linking innate and acquired immunity. Nat Immunol. 2001;2(8):675-80.
Akira S, Uematsu S and Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124(4):783-801.
Alagona P, Jr. Pitavastatin: evidence for its place in treatment of hypercholesterolemia. Core Evid. 2010;5:91-105.
Asehnoune K, Strassheim D, Mitra S, Kim JY and Abraham E. Involvement of reactive oxygen species in Toll-like receptor 4-dependent activation of NF-kappa B. J Immunol . 2004;172(4): 2522-9.
Bachar O, Adner M, Uddman R and Cardell LO. Toll-like receptor stimulation induces airway hyper-responsiveness to bradykinin, an effect mediated by JNK and NF-kappa B signaling pathways. EurJ Immunol . 2004;34(4): 1196-207.
Bains SK, Foresti R, Howard J, Atwal S, Green CJ and Motterlini R. Human sickle cell blood modulates endothelial heme oxygenase activity: effects on vascular adhesion and reactivity. Arterioscler Thromb Vasc Biol. 2010;30(2):305-12.
Bjorkbacka H. Multiple roles of Toll-like receptor signaling in atherosclerosis. Curr Opin Lipidol. 2006;17(5):527-33.
Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol . 2004;5(10):1052-60.
Dauphinee SM and Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Invest. 2006;86(1):9-22.
Dela Paz NG, Melchior B and Frangos JA. Shear stress induces Galphaq/11 activation independently of G protein-coupled receptor activation in endothelial cells. Am J Physiol Cell Physiol. 2017;312(4):428-37.
Dengler TJ, Raftery MJ, Werle M, Zimmermann R and Schonrich G. Cytomegalovirus infection of vascular cells induces expression of pro-inflammatory adhesion molecules by paracrine action of secreted interleukin-1beta. Transplantation. 2000;69(6):1160-8.
Dewberry R, Holden H, Crossman D and Francis S. Interleukin-1 receptor antagonist expression in human endothelial cells and atherosclerosis. Arterioscler Thromb Vasc Biol . 2000;20(11):2394-400.
Fang D, Yang S, Quan W, Jia H, Quan Z and Qu Z. Atorvastatin suppresses Toll-like receptor 4 expression and NF-kappaB activation in rabbit atherosclerotic plaques. Eur Rev Med Pharmacol Sci. 2014;18(2):242-6.
Faure E, Thomas L, Xu H, Medvedev A, Equils O and 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(3):2018-24.
Fotis L, Giannakopoulos D, Stamogiannou L and Xatzipsalti M. Intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in children. Do they play a role in the progression of atherosclerosis? Hormones (Athens). 2012;11(2):140-6.
Frost RA, Nystrom GJ and Lang CH. Lipopolysaccharide regulates proinflammatory cytokine expression in mouse myoblasts and skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 2002;283(3):698-709.
Fukao T and Koyasu S. PI3K and negative regulation of TLR signaling. Trends Immunol. 2003;24(7):358-63.
Gribar SC, Anand RJ, Sodhi CP and Hackam DJ. The role of epithelial Toll-like receptor signaling in the pathogenesis of intestinal inflammation. J Leukoc Biol. 2008;83(3):493-8.
Griendling KK, Sorescu D, Lassegue B and Ushio-Fukai M. Modulation of protein kinase activity and gene expression by reactive oxygen species and their role in vascular physiology and pathophysiology. Arterioscler Thromb Vasc Biol . 2000;20(10):2175-83.
Hsu HY and Wen MH. Lipopolysaccharide-mediated reactive oxygen species and signal transduction in the regulation of interleukin-1 gene expression. J Biol Chem. 2002;277(25):22131-9.
Iiyama K, Hajra L, Iiyama M, Li H, DiChiara M, Medoff BD, et al. Patterns of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 expression in rabbit and mouse atherosclerotic lesions and at sites predisposed to lesion formation. Circ Res. 1999;85(2):199-207.
Kinlay S and Ganz P. Role of endothelial dysfunction in coronary artery disease and implications for therapy. Am J Cardiol. 1997;80(9A):11-16.
Kyriakis JM and Avruch J. Mammalian mitogen-activated protein kinase signal transduction pathways activated by stress and inflammation. Physiol Rev. 2001;81(2):807-69.
Libby P. Inflammation in atherosclerosis. Nature. 2002;420(6917):868-74.
Liu YC, Lo YC, Huang CW and Wu SN. Inhibitory action of ICI-182,780, an estrogen receptor antagonist, on BK(Ca) channel activity in cultured endothelial cells of human coronary artery. Biochem Pharmacol. 2003;66(10):2053-63.
Methe H, Kim JO, Kofler S, Weis M, Nabauer M and Koglin J. Expansion of circulating Toll-like receptor 4-positive monocytes in patients with acute coronary syndrome. Circulation. 2005;111(20):2654-61.
Nishida S, Matsuoka H, Tsubaki M, Tanimori Y, Yanae M, Fujii Y, et al. Mevastatin induces apoptosis in HL60 cells dependently on decrease in phosphorylated ERK. Mol Cell Biochem. 2005;269(1-2):109-14.
Ono K and Han J. The p38 signal transduction pathway: activation and function. Cell Signal. 2000;12(1):1-13.
Pleiner J, Schaller G, Mittermayer F, Zorn S, Marsik C, Polterauer S, et al. Simvastatin prevents vascular hyporeactivity during inflammation. Circulation . 2004;110(21):3349-54.
Raetz CR and Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635-700.
Rice JB, Stoll LL, Li WG, Denning GM, Weydert J, Charipar E, et al. Low-level endotoxin induces potent inflammatory activation of human blood vessels: inhibition by statins. Arterioscler Thromb Vasc Biol . 2003;23(9):1576-82.
Schroder NW and Schumann RR. Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. Lancet Infect Dis. 2005;5(3):156-64.
Sezer ED, Sozmen EY, Nart D and Onat T. Effect of atorvastatin therapy on oxidant-antioxidant status and atherosclerotic plaque formation. Vasc Health Risk Manag. 2011;7:333-43.
Shemesh S, Kamari Y, Shaish A, Olteanu S, Kandel-Kfir M, Almog T, et al. Interleukin-1 receptor type-1 in non-hematopoietic cells is the target for the pro-atherogenic effects of interleukin-1 in apoE-deficient mice. Atherosclerosis. 2012;222(2):329-36.
Simon BC, Noll B and Maisch B. Endothelial dysfunction--assessment of current status and approaches to therapy. Herz. 1999;24(1):62-71.
Sinensky M, Beck LA, Leonard S and Evans R. Differential inhibitory effects of lovastatin on protein isoprenylation and sterol synthesis. J Biol Chem . 1990;265(32):19937-41.
Takemoto M and Liao JK. Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors. Arterioscler Thromb Vasc Biol . 2001;21(11):1712-9.
Tousoulis D, Antoniades C, Koumallos N and Stefanadis C. Pro-inflammatory cytokines in acute coronary syndromes: from bench to bedside. Cytokine Growth Factor Rev. 2006;17(4): 225-33.
Wang L, Zhang X, Liu L, Yang R, Cui L and Li M. Atorvastatin protects rat brains against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors (RAGE and TLR4), NF-kappaB expression. Neurosci Lett. 2010;471(3):152-6.
Wang Y, Zhang MX, Meng X, Liu FQ, Yu GS, Zhang C, et al. Atorvastatin suppresses LPS-induced rapid upregulation of Toll-like receptor 4 and its signaling pathway in endothelial cells. Am J Physiol Heart Circ Physiol. 2011;300(5):1743-52.
Weis M, Pehlivanli S, Meiser BM and von Scheidt W. Simvastatin treatment is associated with improvement in coronary endothelial function and decreased cytokine activation in patients after heart transplantation. J Am Coll Cardiol. 2001;38(3):814-8.
Wiedermann CJ, Kiechl S, Dunzendorfer S, Schratzberger P, Egger G, Oberhollenzer F, et al. Association of endotoxemia with carotid atherosclerosis and cardiovascular disease: prospective results from the Bruneck Study. J Am Coll Cardiol . 1999;34(7):1975-81.
Xu XH, Shah PK, Faure E, Equils O, Thomas L, Fishbein MC, et al. Toll-like receptor-4 is expressed by macrophages in murine and human lipid-rich atherosclerotic plaques and upregulated by oxidized LDL. Circulation . 2001;104(25):3103-8.
Yamagami H, Yamagami S, Inoki T, Amano S and Miyata K. The effects of proinflammatory cytokines on cytokine-chemokine gene expression profiles in the human corneal endothelium. Invest Ophthalmol Vis Sci. 2003;44(2):514-20.
Yang SS, Li R, Qu X, Fang W and Quan Z. Atorvastatin decreases Toll-like receptor 4 expression and downstream signaling in human monocytic leukemia cells. Cell Immunol. 2012;279(1):96-102.
Yoon JJ, Lee YJ, Kim JS, Kang DG and Lee HS. Protective role of betulinic acid on TNF-alpha-induced cell adhesion molecules in vascular endothelial cells. Biochem Biophys Res Commun. 2010;391(1):96-101.
Zarember KA and Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol . 2002;168(2):554-61.
Downloads
Publicado
Edição
Seção
Licença
Este trabalho está licenciado sob uma licença Creative Commons Attribution 4.0 International License.
All content of the journal, except where identified, is licensed under a Creative Commons attribution-type BY.
The on line journal has open and free access.