Transforming Growth Factor-β
2001; Lippincott Williams & Wilkins; Volume: 89; Issue: 10 Linguagem: Inglês
10.1161/res.89.10.853
ISSN1524-4571
AutoresEsther Lutgens, Mat J.A.P. Daemen,
Tópico(s)Galectins and Cancer Biology
ResumoHomeCirculation ResearchVol. 89, No. 10Transforming Growth Factor-β Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTransforming Growth Factor-βA Local or Systemic Mediator of Plaque Stability? Esther Lutgens and Mat J.A.P. Daemen Esther LutgensEsther Lutgens From the Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, the Netherlands. and Mat J.A.P. DaemenMat J.A.P. Daemen From the Department of Pathology, Cardiovascular Research Institute Maastricht, University of Maastricht, the Netherlands. Originally published3 Apr 2018https://doi.org/10.1161/res.89.10.853Circulation Research. 2001;89:853–855Atherosclerosis is mainly considered to be a chronic inflammatory disease.1,2 The importance of inflammatory mediators in the initiation and progression of atherosclerosis is reflected by the composition of the atherosclerotic lesion and by many intervention studies in mouse models of atherosclerosis. Activated macrophages and T-lymphocytes are already observed in fatty streak lesions,3 and the contribution of inflammatory cells and mediators increases when the atherosclerotic lesion progresses.4 Furthermore, intervention studies in atherosclerotic mouse models that inhibit major (anti)inflammatory mediators such as CD40L,5–9 gm-CSF,10,11 MCP1,12 IFNγ,13 and IL-1014,15 have a profound effect on lesion initiation, progression, and plaque composition.So far, IL-10 is the only antiinflammatory cytokine that has been reported to be protective in atherosclerosis.15,16 In the present issue of Circulation Research, the study by Mallat et al17 showed that inhibition of the antiinflammatory cytokine transforming growth factor (TGF)-β resulted in an acceleration of atherosclerosis. Moreover, atherosclerotic lesions exhibited an increased inflammatory cell content and a decrease in collagen content, which are features of plaque instability. The data of Mallat et al indicate that TGF-β plays a protective role in the initiation of atherosclerosis and may be an important factor for the maintenance of plaque stability.The feature that inhibition of inflammatory mediators or stimulation of antiinflammatory mediators modulate atherosclerotic plaque stability has already been shown in several studies. For example, interventions in atherosclerotic mouse models with major inflammatory regulators such as CD40L,5,6,8,9 IFNγ,13 and IL1014 are able to modulate features of plaque stability, such as the amount of inflammation and fibrosis. IFNγ −/−/ApoE −/− mice show a decreased inflammatory cell content and an increased collagen-content,13 whereas inhibition of the antiinflammatory cytokine IL-10 showed the reverse.14The inflammatory mediator with the most profound effect on plaque stability is CD40L. Besides a profound decrease in plaque area, deficiency of a functional CD40L gene resulted in a less lipid-containing, collagen- and smooth muscle cell–rich plaque phenotype, with a reduced macrophage and T-lymphocyte content in their advanced atherosclerotic plaques.5,7 In follow-up studies, pharmacological interruption of CD40L-CD40 signaling (anti-CD40L antibody) induced a quite similar phenotype.6,7,9 This phenotype could even be established when the antibody treatment was delayed until advanced plaques had developed.Further dissection of the pathways involved in the development of the stable plaque phenotype revealed an increased immunoreactivity of TGF-β.6 These data suggest a key role for TGF-β in the development of a stable plaque phenotype during CD40L inhibition. Moreover, with the data of Mallat et al,17 a key role for TGF-β in the regulation of plaque stability in general can been proposed.The first evidence for an important role for TGF-β in vascular biology has been shown in studies in the balloon-injured rat carotid artery, a model for neointima formation. TGF-β levels had increased during the first day after the procedure.18 Furthermore, overexpression or inhibition of TGF-β influenced the extent of neointima formation, extracellular matrix deposition, or smooth muscle cell proliferation.19,20Although the effects of TGF-β on neointimal formation have been extensively investigated, data regarding the effects of TGF-β on primary atherosclerosis are still limited and, moreover, solely descriptive. The localization of the different isoforms of TGF-β and its receptors in the atherosclerotic plaque are well described. TGF-β1 and -β3 are present in all stages of atherosclerosis and are predominantly expressed by the macrophage and the smooth muscle cell.21,22 On the other hand, TGF-βRI and -βRII are abundantly present in fatty streaks, whereas only low, patchy expression is observed in advanced atherosclerotic lesions.23 Interestingly, mutations in the TGF-βRII that disable proper signaling in atherosclerotic lesions have also been reported by some,21 but not all,24 indicating that absence of TGF-β contributes to disease progression.21In vivo studies investigating the effects of TGF-β on atherosclerosis are sparse. ApoE −/− mice that were treated with tamoxifen (an antiestrogen) exhibited increased levels of TGF-β, which was associated with a decrease in initial plaque area.25 In addition, TGF-β1 +/− mice that were treated with high cholesterol diet showed increased endothelial activation and lipid retention compared with TGF-β1 +/+ mice.26 The first in vivo correlation between plaque rupture and TGF-β was reported by Grainger et al,27 who showed that humans suffering from unstable angina have decreased plasma levels of TGF-β. However, the study by Mallat et al is the first in vivo intervention study that describes the effects of TGF-β in plaque progression and phenotype in primary atherosclerosis.Mallat et al treated ApoE −/− mice for a long period (9 weeks) with a neutralizing antibody that inhibits TGF-β1, -β2, and -β3. As may be expected from such an approach, they did observe systemic effects.17 The authors correctly mention in the article that some of these systemic effects of anti–TGF-β treatment might have confounded their results. Indeed, besides the effects of TGF-β inhibition on inflammation and fibrosis in atherosclerotic lesions, treatment also induced inflammatory changes in the heart and resulted in a 3-fold increase in CD3-positive cells in the adventitia, suggesting a systemic vasculitis. Therefore, the question raises whether the systemic effects are due to local inhibition of TGF-β or a generalized immunosuppression. Mallat et al were able to find decreased levels of phospho-Smad2, indicating that the effects were mediated by TGF-β17; however, measurement of systemic inflammatory parameters in serum, such as CRP, TNFα, IL-6, etc, and whole body autopsy would have been more appropriate to exclude systemic inflammation.As has been reported, vasculitis, as well as other systemic inflammatory diseases, are able to accelerate and aggravate atherosclerosis. Patients suffering from Takayasu arteritis have an increased incidence of advanced atherosclerotic lesions compared to their age matched controls.28 This is also true for patients suffering from systemic lupus erythematosus (SLE). In both the carotid and coronary arteries of patients with SLE, the extent of atherosclerosis is 30% to 50% more than in age matched controls. 29,30 In a large prospective population study (Bruneck Study31), it was shown that even common infections, such as respiratory infections, urinary tract infections, dental infections, or other infections, amplify the risk of atherosclerosis. Atherosclerotic risk was highest among subjects with chronic infections. Furthermore, the association between chlamydia pneumonia infection and atherosclerosis is also thought to result from systemic inflammation rather than from direct infection of the atherosclerotic plaque.32Using a different approach, we found similar results as reported by Mallat et al.17 In a recent study, we treated ApoE −/− mice with a murine TGF-βRII fusion protein (TGF-βRII:Fc), which acts as a competitive inhibitor of TGF-β signaling (data will be presented at the Scientific Sessions of the AHA, November 2001). As Mallat et al have shown,17 we also observed a profound increase in inflammatory cells and mediators in initial and advanced atherosclerotic plaques after TGF-β inhibition, whereas the amount of fibrosis had decreased. Moreover, in advanced atherosclerotic plaques, the increase in inflammation and decrease in fibrosis in plaques were associated with a significant increase in the frequencies of recent and older intraplaque bleedings, fibrin deposition, iron deposition, and small plaque ruptures with disruption of the endothelial coverage after TGF-βRII:Fc treatment.These data provide in vivo evidence that inhibition of TGF-β signaling induces characteristics of plaque instability in mouse atherosclerotic plaques. The data indicate that TGF-β plays an important role as immunomodulator and in extracellular matrix biology in atherosclerotic lesions. Thus, activation of TGF-β–signaling may provide a therapeutic target in atherosclerosis. It might not prevent the initiation of atherosclerosis, but it may prevent the transition into an unstable plaque phenotype due to its immunosuppressive and profibrotic effects.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.E.L. is a postdoctoral fellow of the Dr E. Dekker program of the Dutch Heart Foundation (D2000-42).FootnotesCorrespondence to Mat J.A.P. Daemen, Dept of Pathology, P. Debeyelaan 25, 6202 AZ Maastricht, Netherlands. E-mail [email protected] References 1 Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med. 1999; 340: 115–126.CrossrefMedlineGoogle Scholar2 Class CK, Witztum JL. Atherosclerosis: the road ahead. Cell. 2001; 104: 503–516.CrossrefMedlineGoogle Scholar3 Emeson EE, Robertson AL. T lymphocytes in aortic and coronary intimas: their potential role in atherogenesis. Am J Pathol. 1988; 130: 369–376.MedlineGoogle Scholar4 Virmani R, Kolodgie FD, Burke AP, Farb A, Schwartz SM. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol. 2000; 20: 1262–1275.CrossrefMedlineGoogle Scholar5 Lutgens E, Gorelik L, Daemen MJAP, de Muinck ED, Grewal IS, Kotelianski VE, Flavell RA. Requirement for CD154 in the progression of atherosclerosis. Nat Med. 1999; 5: 1313–1316.CrossrefMedlineGoogle Scholar6 Lutgens E, Cleutjens KBJM, Heeneman S, Koteliansky VE, Burkly LC, Daemen MJAP. Both early and delayed anti-CD40L antibody treatment induces a stable plaque phenotype. Proc Natl Acad Sci U S A. 2000; 97: 7464–7469.CrossrefMedlineGoogle Scholar7 Lutgens E, Daemen MJAP. CD40-CD40L interactions in atherosclerosis. Trends Cardiovasc Med. 2001. In press.Google Scholar8 Mach F, Schönbeck U, Sukhova GK, Atkinson E, Libby P. Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature. 1998; 394: 200–203.CrossrefMedlineGoogle Scholar9 Schönbeck U, Sukhova GK, Shimizu K, Mach F, Libby P. Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A. 2000; 97: 7458–7463.CrossrefMedlineGoogle Scholar10 Qiao J, Tripathi J, Mishra NK, Cai Y, Tripathi S, Wang X, Imes S, Fishbein MC, Clinton SK, Libby P, Lusis AJ, Rajavashisth TB. Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol. 1997; 150: 1687–1699.MedlineGoogle Scholar11 Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N, Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis A. Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor–deficient mice. J Clin Invest. 101: 2702–2710.CrossrefMedlineGoogle Scholar12 Aiello RJ, Bourassa PAK, Lindsey S, Weng W, Natoli E, Rollins BJ, Milos P. Monocyte chemoattractant protein-1 accelerates atherosclerosis in apolipoprotein E-deficient mice. Arterioscler Thromb Vasc Biol. 1999; 19: 1518–1525.CrossrefMedlineGoogle Scholar13 Gupta S, Pablo AM, Jiang XC, Wang N, Tall AR, Schindler C. IFN-γ potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest. 1997; 99: 2752–2761.CrossrefMedlineGoogle Scholar14 Pinderski Oslund LJ, Hedrick CC, Olvera T, Hagenbaugh A, Territo M, Berliner JA, Fyfe AI. Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol. 1999; 19: 2847–2853.CrossrefMedlineGoogle Scholar15 Mallat Z, Besnard S, Duriez M, Deleuze V, Emmanuel F, Bureau MF, Soubrier F, Esposito B, Duez H, Fievet C, Staels B, Duverger N, Scherman D, Tedgui A. Protective role of interleukin-10 in atherosclerosis. Circ Res. 1999; 85: e17–e24.CrossrefMedlineGoogle Scholar16 Lamontagne D, Pohl U, Busse R. Mechanical deformation of vessel wall and shear stress determine the basal release of endothelium-derived relaxing factor in the intact rabbit coronary vascular bed. Circ Res. 1992; 70: 123–130.CrossrefMedlineGoogle Scholar17 Mallat Z, Gojova A, Marchiol-Fournigault C, Esposito B, Kamaté C, Merval R, Fradelizi D, Tedgui A. Inhibition of transforming growth factor-β signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res. 2001; 89: 930–934.CrossrefMedlineGoogle Scholar18 Majesky MW, Lindner V, Twardizik DR, Schwartz SM, Reidy MA. Production of transforming growth factor-β1 during repair of arterial injury. J Clin Invest. 1991; 88: 904–910.CrossrefMedlineGoogle Scholar19 Schulick AH, Taylor AJ, Zuo W, Qiu C, Dong G, Woodward RN, Agah R, Roberts AB, Virmani R, Dichek DA. Overexpression of transforming growth factor-β1 in arterial endothelium causes hyperplasia, apoptosis and cartilaginous metaplasia. Proc Natl Acad Sci U S A. 1998; 95: 6983–6988.CrossrefMedlineGoogle Scholar20 Smith JD, Bryant SR, Couper LL, Vary CPH, Gotwals PJ, Koteliansky VE, Lindner V. Soluble transforming growth factor-β type II receptor inhibits negative remodeling, fibroblast differentiation and intimal lesion formation, but not endothelial growth. Circ Res. 1999; 84: 1212–1222.CrossrefMedlineGoogle Scholar21 McCaffrey TA. TGFβs and TGFβ receptors in atherosclerosis. Cytokine Growth Factor Rev. 2000; 11: 103–114.CrossrefMedlineGoogle Scholar22 McCaffrey TA, Du B, Fu C, Bray PJ, Sanborn TA, Deutsch E, Tarazona N Shaknovitch A, Newman G, Patterson C, Bush HL. The expression of TGFβ receptors in human atherosclerosis: evidence for acquired resistance to apoptosis due to receptor imbalance. J Mol Cell Cardiol. 1999; 31: 1627–1642.CrossrefMedlineGoogle Scholar23 Bobik A, Agrotis A, Kanellakis P, Dilley R, Krushinsky A, Smirnov V, Tararak E, Condron M, Kostolias G. Distinct patterns of Transforming growth factor-β isoform and receptor expression in human atherosclerotic lesions: colocalization implicates TGF-β in fibrofatty lesion development. Circulation. 1999; 99: 2883–2891.CrossrefMedlineGoogle Scholar24 Clark KJ, Cary NR, Grace AA, Metcalfe JC. Microsatellite mutation of type II transforming growth factor-β receptor is rare in atherosclerotic plaques. Arterioscler Thromb Vasc Biol. 2001; 21: 555–559.CrossrefMedlineGoogle Scholar25 Reckless J, Metcalfe JC, Grainger DJ. Tamoxifen decreases cholesterol sevenfold and abolishes lipid lesion development in apolipoprotein E knockout mice. Circulation. 1997; 95: 1542–1548.CrossrefMedlineGoogle Scholar26 Grainger DJ, Mosedale DE, Metcalfe JC, Bottinger EP. Dietary fat and reduced levels of TGFβ1 act synergistically to promote activation of the vascular endothelium and formation of lipid lesions. J Cell Sci. 2000; 113: 2355–2361.CrossrefMedlineGoogle Scholar27 Grainger DJ, Kemp PR, Metcalfe JC, Liu AC, Lawn RM, Williams NR, Grace AA, Schofield PM, Chauhan A. The serum concentration of active transforming growth factor-β is severely depressed in advanced atherosclerosis. Nat Med. 1995; 1: 74–79.CrossrefMedlineGoogle Scholar28 Numano F, Kishi Y, Tanaka A, Ohkawara M, Kakuta T, Kobayashi Y. Inflammation and atherosclerosis: atherosclerotic lesions in Takayasu arteritis. Ann N Y Acad Sci. 2000; 902: 65–76.MedlineGoogle Scholar29 Roman MJ, Salmon JE, Sobel R, Lockshin MD, Sammaritano L, Schwartz JE, Devereux RB. Prevalence and relation to risk factors of carotid artery atherosclerosis and left ventricular hypertrophy in systemic lupus erythematosus and antiphospholipid antibody syndrome. Am J Cardiol. 2001; 87: 663–666.CrossrefMedlineGoogle Scholar30 Karrar A, Sequeira W, Block JA. Coronary artery disease in systemic lupus erythematosus: a review of the literature. Semin Arthritis Rheum. 2001; 30: 436–443.CrossrefMedlineGoogle Scholar31 Kiechl S, Egger G, Mayr M, Wiedermann CJ, Bonora E, Oberhollenzer F, Muggeo M, Xu Q, Wick G, Poewe W, Willeit J. Chronic infections and the risk of carotid atherosclerosis: prospective results from a large population study. Circulation. 2001; 103: 1064–1070.CrossrefMedlineGoogle Scholar32 Virok D, Kis Z, Karai L, Intzedy L, Burian K, Szabo A, Ivanyi B, Gonczol E. Chlamydia pneumoniae in atherosclerotic middle cerebral artery. Stroke. 2001; 32: 1973–1978.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Yang H, Li H, Chen W, Mei Z, Yuan Y, Wang X, Chu L, Xu Y, Sun Y, Li D, Gao H, Zhan B, Li H and Yang X (2021) Therapeutic Effect of Schistosoma japonicum Cystatin on Atherosclerotic Renal Damage, Frontiers in Cell and Developmental Biology, 10.3389/fcell.2021.760980, 9 Rey N, Ebrahimian T, Gloaguen C, Kereselidze D, Magneron V, Bontemps C, Demarquay C, Olsson G, Haghdoost S, Lehoux S and Ebrahimian T (2021) Exposure to Low to Moderate Doses of Ionizing Radiation Induces A Reduction of Pro-Inflammatory Ly6chigh Monocytes and a U-Curved Response of T Cells in APOE -/- Mice, Dose-Response, 10.1177/15593258211016237, 19:2, (155932582110162), Online publication date: 1-Apr-2021. Gorabi A, Kiaie N, Sathyapalan T, Al-Rasadi K, Jamialahmadi T and Sahebkar A (2020) The Role of MicroRNAs in Regulating Cytokines and Growth Factors in Coronary Artery Disease: The Ins and Outs, Journal of Immunology Research, 10.1155/2020/5193036, 2020, (1-10), Online publication date: 25-Jul-2020. Fatkhullina A, Peshkova I and Koltsova E (2016) The role of cytokines in the development of atherosclerosis, Biochemistry (Moscow), 10.1134/S0006297916110134, 81:11, (1358-1370), Online publication date: 1-Nov-2016. Ren J, Zhang J, Xu N, Han G, Geng Q, Song J, Li S, Zhao J, Chen H and Beltrami A (2013) Signature of Circulating MicroRNAs as Potential Biomarkers in Vulnerable Coronary Artery Disease, PLoS ONE, 10.1371/journal.pone.0080738, 8:12, (e80738) Koltsova E, Kim G, Lloyd K, Saris C, von Vietinghoff S, Kronenberg M and Ley K (2012) Interleukin-27 Receptor Limits Atherosclerosis in Ldlr−/− Mice, Circulation Research, 111:10, (1274-1285), Online publication date: 26-Oct-2012.Ait-Oufella H, Taleb S, Mallat Z and Tedgui A (2011) Recent Advances on the Role of Cytokines in Atherosclerosis, Arteriosclerosis, Thrombosis, and Vascular Biology, 31:5, (969-979), Online publication date: 1-May-2011. Zhang G, Marshall A, Thomas A, Kernan K, Su Y, LeBoeuf R, Dong X and Tchao B (2011) In vivo knockdown of nicotinic acetylcholine receptor α1 diminishes aortic atherosclerosis, Atherosclerosis, 10.1016/j.atherosclerosis.2010.07.057, 215:1, (34-42), Online publication date: 1-Mar-2011. Johnson J (2014) Matrix metalloproteinases: influence on smooth muscle cells and atherosclerotic plaque stability, Expert Review of Cardiovascular Therapy, 10.1586/14779072.5.2.265, 5:2, (265-282), Online publication date: 1-Mar-2007. Horwitz M, Knudsen M, Ilic A, Fine C and Sarvetnick N (2006) Transforming Growth Factor- β Inhibits Coxsackievirus-Mediated Autoimmune Myocarditis , Viral Immunology, 10.1089/vim.2006.19.722, 19:4, (722-733), Online publication date: 1-Dec-2006. CRIVELLO A (2006) Frequency of Polymorphisms of Signal Peptide of TGF-beta1 and -1082G/A SNP at the Promoter Region of Il-10 Gene in Patients with Carotid Stenosis, Annals of the New York Academy of Sciences, 10.1196/annals.1354.038, 1067:1, (288-293), Online publication date: 1-May-2006. Otsuka G, Agah R, Frutkin A, Wight T and Dichek D (2005) Transforming Growth Factor Beta 1 Induces Neointima Formation Through Plasminogen Activator Inhibitor-1–Dependent Pathways, Arteriosclerosis, Thrombosis, and Vascular Biology, 26:4, (737-743), Online publication date: 1-Apr-2006. Tedgui A and Mallat Z (2006) Cytokines in Atherosclerosis: Pathogenic and Regulatory Pathways, Physiological Reviews, 10.1152/physrev.00024.2005, 86:2, (515-581), Online publication date: 1-Apr-2006. Lutgens E, Lutgens S, Faber B, Heeneman S, Gijbels M, de Winther M, Frederik P, van der Made I, Daugherty A, Sijbers A, Fisher A, Long C, Saftig P, Black D, Daemen M and Cleutjens K (2005) Disruption of the Cathepsin K Gene Reduces Atherosclerosis Progression and Induces Plaque Fibrosis but Accelerates Macrophage Foam Cell Formation, Circulation, 113:1, (98-107), Online publication date: 3-Jan-2006.Kalinina N, Agrotis A, Antropova Y, Ilyinskaya O, Smirnov V, Tararak E and Bobik A (2004) Smad Expression in Human Atherosclerotic Lesions, Arteriosclerosis, Thrombosis, and Vascular Biology, 24:8, (1391-1396), Online publication date: 1-Aug-2004. Daugherty A (2002) Atherosclerosis: cell biology and lipoproteins, Current Opinion in Lipidology, 10.1097/00041433-200208000-00015, 13:4, (453-455), Online publication date: 1-Aug-2002. Lutgens E, Gijbels M, Smook M, Heeringa P, Gotwals P, Koteliansky V and Daemen M (2002) Transforming Growth Factor-β Mediates Balance Between Inflammation and Fibrosis During Plaque Progression, Arteriosclerosis, Thrombosis, and Vascular Biology, 22:6, (975-982), Online publication date: 1-Jun-2002. Michon I, Penning L, Molenaar T, van Berkel T, Biessen E and Kuiper J (2002) The effect of TGF-β receptor binding peptides on smooth muscle cells, Biochemical and Biophysical Research Communications, 10.1016/S0006-291X(02)00378-9, 293:4, (1279-1286), Online publication date: 1-May-2002. November 9, 2001Vol 89, Issue 10 Advertisement Article InformationMetrics https://doi.org/10.1161/res.89.10.853PMID: 11701610 Originally publishedApril 3, 2018 Keywordsunstable plaquefibrosisinflammationtransforming growth factor-βatherosclerosisPDF download Advertisement
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