Allograft Arteriosclerosis and Immune-Driven Angiogenesis
2003; Lippincott Williams & Wilkins; Volume: 107; Issue: 9 Linguagem: Norueguês
10.1161/01.cir.0000059744.64373.08
ISSN1524-4539
AutoresPeter Libby, David Xiao-Ming Zhao,
Tópico(s)Angiogenesis and VEGF in Cancer
ResumoHomeCirculationVol. 107, No. 9Allograft Arteriosclerosis and Immune-Driven Angiogenesis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBAllograft Arteriosclerosis and Immune-Driven Angiogenesis Peter Libby, MD and David Xiao-Ming Zhao, MD Peter LibbyPeter Libby From the Leducq Center of Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (P.L.); and Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn (D.X.-M.Z.). and David Xiao-Ming ZhaoDavid Xiao-Ming Zhao From the Leducq Center of Cardiovascular Research, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (P.L.); and Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tenn (D.X.-M.Z.). Originally published11 Mar 2003https://doi.org/10.1161/01.CIR.0000059744.64373.08Circulation. 2003;107:1237–1239During most of the last century, the concept of atherosclerosis as a cholesterol storage disease prevailed.1 By the mid-1980s, it had become clear that in addition to lipid-engorged macrophage foam cells, cells of the adaptive immune response, particularly T lymphocytes, localized in atheromatous lesions.2 These observations raised the possibility that immune and inflammatory processes might participate in atherogenesis. However, it remained unclear whether the immune response in atherosclerosis simply followed cholesterol-inflicted damage or could possibly play a more primary role in arterial disease.See p 1308As can happen when the experimentalist maintains clinical contact, observation of the patient afforded a perspective on this puzzle. The adoption of cardiac transplantation created a new disease: accelerated coronary arteriosclerosis.3 Even in recipients with nonischemic cardiomyopathy and normal lipids, an aggressive form of intimal disease could narrow epicardial and intramyocardial coronary branches and all too often threaten graft survival. We have preferred the term arteriosclerosis (hardening of the arteries) to atherosclerosis (gruel in the arteries) because the allograft coronary artery lesions often lack a lipid-rich core typical of atheroma.This iatrogenic disease provided a strong indication that immune activation could induce explosive intimal disease even in the absence of a strong lipid stimulus. Most cases of atherosclerosis depend at least in part on dyslipidemia. At one end of the spectrum, a child whose only risk factor is elevated low-density lipoprotein (LDL) due to homozygous familial hypercholesterolemia can develop severe atherosclerosis in the first decade of life (Figure).4 However, allograft coronary disease taught us that at the other extreme, immune factors themselves could lead to arteriopathy even in the absence of classical lipid risk factors (Figure). Just as study of familial hypercholesterolemia led to epochal advances in our understanding of lipid-driven atherosclerosis, we reasoned that close scrutiny of allograft arterial disease could furnish new insight into immune and inflammatory mechanisms of arterial disease. Download figureDownload PowerPointAllograft arteriosclerosis: one end of the continuum. This diagram depicts atherosclerosis as a continuum between two extremes. Accelerated arteriosclerosis can occur in the allografted heart in the absence of traditional coronary risk factors (far left side). This disease probably involves a primarily immune-mediated pathogenesis of arterial intimal disease. The other extreme (far right side) represents the case of a child who may succumb to rampant atherosclerosis in the first decade of life due solely to an elevated LDL caused by a mutation in the LDL receptor (homozygous familial hypercholesterolemia). Between these two extremes lie the vast majority of patients with atherosclerosis, probably involving various mixtures of immune and inflammatory and/or lipoprotein-mediated disease. One can further consider that this diagram extends to a third dimension that would involve other candidate risk factors such as homocysteine, lipoprotein(a), infection, tobacco abuse, and so on. Reproduced with permission. From: The vascular biology of atherosclerosis. In: Braunwald E, Zipes DP, Libby P, eds. Heart Disease: A Text Book of Cardiovascular Medicine. Philadelphia, Pa: W.B. Saunders; 2001:995–1009.An early scheme of the pathogenesis of allograft arteriopathy posited a pivotal role for an immune response directed against foreign transplantation antigens as the trigger to a cytokine cascade that wrought the arterial damage.5 Renal transplanters recognized graft arteriopathy as "chronic rejection." Hypothesizing that the mechanism of allograft arteriopathy differs fundamentally from myocardial rejection, we rejected that term (Table).6 Myocytolysis characterizes parenchymal rejection. Cytolytic T cells, the effector arm of the cellular immune response, mediate this lethal damage to cardiac myocytes. These killer T cells usually bear the CD8 marker and recognize their target cells by an interaction that involves class I transplantation antigens. In stark contrast, a fibroproliferative, not cytolytic, reaction typifies allograft arteriopathy. Much evidence points to a helper T cell–dependent and cytokine- and growth factor–mediated mechanism for development of this type of arterial lesion. The helper T cells usually bear the CD4 marker and recognize their target cells by an interaction that involves class II transplantation antigens (a reaction termed the allogeneic response). This postulated pathogenic pathway for allograft arteriopathy, first proposed in 1989,5 has withstood the test of time. Experiments in genetically altered mice increasingly support this model.7,8 Moreover, such experiments often show disparity in the effects of various mutations on parenchymal versus arterial disease, supporting the fundamental mechanistic differences noted above.8,9Cardiac Allograft Parenchymal Rejection Versus ArteriopathyParenchymal RejectionAllograft ArteriopathyHistological hallmark:MyocytolysisFibro-proliferationMajor effector cell:Killer T cell (CD8+)Helper T cell (CD4+)Recognition structure for T lymphocytes:Class I histocompatibility antigenClass II histocompatibility antigenIf immune-mediated reactions cause allograft arteriopathy, why don't the immunosuppressants taken by transplantation recipients prevent the disease? The usual menu of drugs currently used actually succeeds in preventing parenchymal rejection for the most part. However, cyclosporin poorly suppressed the ability of foreign endothelial cells to engender a cellular immune response in vitro.10How then can we combat allograft arteriopathy in the clinic? This disease still represents a major limitation to the long-term success of cardiac transplantation and remains a pressing clinical problem. Perhaps more effective immunosuppressive regimens will prove better able to inhibit this process. Indeed, rapamycin may inhibit the immune response to foreign endothelial cells more effectively than cyclosporin. Statin treatment seems to limit the disease, perhaps in part because of effects independent of lipid lowering.11,12 Allograft arteriopathy, however, has far from disappeared and thus requires new therapies.The recognition of the inflammatory nature of graft coronary disease suggests that antiinflammatory strategies might help. In this issue of Circulation, Nykänen et al13 show that angiopoietin-1 can protect against the development of arteriosclerosis in allografted rat hearts. Their previous work14 showed that vascular endothelial growth factor (VEGF) enhanced formation of these lesions. In their current article,13 they show that its endogenous antagonist, angiopoietin-1, can forestall lesion formation. These observations draw attention to the role of microvessels in this disease.Microvessels populate many human atheroma and the arterial lesions in some lipid-driven models of atherosclerosis as well.15 Anti-angiogenic strategies can limit experimental atherogenesis, and the results of Nykänen et al13 extend this concept to allograft vasculopathy. However, the story of the microvasculature in allografts is even more complex than in usual atherosclerosis. Experiments performed a decade ago showed more exuberant angiogenesis in allografted arteries than in native arteries.16 We compared arterial lesions in heterotopic cardiac allografts and the native heart in hypercholesterolemic rabbits. Both hearts experienced the identical lipid milieu, yet the expanded intima in the allografted arteries contained many more microvessels and T lymphocytes than those in the recipients' own arteries. These observations suggested that the allogenic immune response accentuated angiogenesis during atherogenesis. Later studies showed that during the allogeneic response in vitro, T lymphocytes produce angiogenic growth factors including VEGF.17,18 Thus, the observations of Nykänen et al13 may have particular relevance to this special form of arteriosclerosis. In addition to angiopoietin, transplanted hearts can overexpress another endogenous modulator of angiogenesis. Human cardiac allografts overexpress thrombospondin-1 (TSP-1), an extracellular matrix glycoprotein that inhibits angiogenesis and facilitates smooth muscle cell proliferation. Significant elevation of TSP-1 in cardiac allografts associates with the severity of cardiac allograft arteriosclerosis. Smooth muscle cells from the luminal (inner) layer of the expanded intima intensely express TSP-1, whereas the greatest VEGF expression occurs in infiltrating inflammatory cells in the abluminal (outer) layers of the intima. Neovascularization co-localizes with VEGF-producing cells and is sparse in areas with intense TSP-1 expression. These data suggest that angiogenesis modulators, such as TSP-1, inhibit angiogenesis and promote smooth muscle cell proliferation, processes that promote transplantation arteriopathy.18What lessons can we draw from the tale of transplantation arteriopathy? First, the life-saving procedure of cardiac transplantation comes with a biological cost — a risk of obliterative arteriopathy — that too often replaces one disease with another.Second, by studying the rarer but extreme forms of disease, we can gain insight into the pathogenesis of the more common but often multifactorial afflictions. Indeed, most cases of "usual" atherosclerosis likely lie between the two poles of strictly immune-dependent allograft arteriopathy and the solely lipid-driven lesions in the young familial hypercholesterolemic patient (Figure). In most atherosclerotic patients, a mix of lipid disorders and immune and inflammatory factors conspire to promote the disease.Third, we must remember that angiogenesis can cut both ways in arteriosclerosis. Formation of neovessels in the lesion may sustain its growth and provide a portal for entry of inflammatory cells. These potential adverse actions of angiogenic therapy for atherosclerosis merit thoughtful consideration.Fourth, opposing forces are the norm in biology; in this case, the actions of anti-angiogenic and antiinflammatory factors can countervail the heightened angiogenic response in the transplanted artery.Finally, by picking apart the fundamental details of disease pathogenesis, we may identify new therapeutic targets that will aid us in treating patients. When we really understand myocardial failure and atherosclerosis, we won't need to transplant hearts. Until then, we must strive to understand and overcome allograft arterial disease.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.Dr Libby is supported in part by a grant from the National Heart, Lung and Blood Institute (HL-43364).FootnotesCorrespondence to Peter Libby, MD, Brigham and Women's Hospital, 221 Longwood Ave, Eugene Braunwald Research Center 307, Boston, MA 02115. E-mail [email protected] References 1 Ross R, Harker L. Hyperlipidemia and atherosclerosis. Science. 1976; 193: 1094–1100.CrossrefMedlineGoogle Scholar2 Libby P, Hansson GK. Involvement of the immune system in human atherogenesis: current knowledge and unanswered questions. Lab Invest. 1991; 64: 5–15.MedlineGoogle Scholar3 Billingham ME. Cardiac transplant atherosclerosis. Transplant Proc. 1987; 19: 19–25.MedlineGoogle Scholar4 Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986; 232: 232–247.CrossrefMedlineGoogle Scholar5 Libby P, Salomon RN, Payne DD, et al. Functions of vascular wall cells related to the development of transplantation-associated coronary arteriosclerosis. Transplant Proc. 1989; 21: 3677–3684.MedlineGoogle Scholar6 Libby P. Transplantation-associated arteriosclerosis: potential mechanisms. In: Tilney N, Strom T, eds. Transplantation Biology. Philadelphia, Pa: Lippincott-Raven Publishers; 1996:577–586.Google Scholar7 Shi C, Lee WS, He Q, et al. Immunologic basis of transplant-associated arteriosclerosis. Proc Natl Acad Sci U S A. 1996; 93: 4051–4056.CrossrefMedlineGoogle Scholar8 Nagano H, Mitchell RN, Taylor MK, et al. Interferon-gamma deficiency prevents coronary arteriosclerosis but not myocardial rejection in transplanted mouse hearts. J Clin Invest. 1997; 100: 550–557.CrossrefMedlineGoogle Scholar9 Shimizu K, Schonbeck U, Mach F, et al. Host CD40 ligand deficiency induces long-term allograft survival and donor-specific tolerance in mouse cardiac transplantation but does not prevent graft arteriosclerosis. J Immunol. 2000; 165: 3506–3518.CrossrefMedlineGoogle Scholar10 Karmann K, Pober JS, Hughes CC. Endothelial cell-induced resistance to cyclosporin A in human peripheral blood T cells requires contact-dependent interactions involving CD2 but not CD28. J Immunol. 1994; 153: 3929–3937.MedlineGoogle Scholar11 Kobashigawa JA, Katznelson S, Laks H, et al. Effect of pravastatin on outcomes after cardiac transplantation. N Engl J Med. 1995; 333: 621–627.CrossrefMedlineGoogle Scholar12 Wenke K, Meiser B, Thiery J, et al. Simvastatin reduces graft vessel disease and mortality after heart transplantation: a four-year randomized trial. Circulation. 1997; 96: 1398–1402.LinkGoogle Scholar13 Nykänen AI, Krebs R, Saaristo A. Angiopoietin-1 protects against the development of cardiac allograft arteriosclerosis. Circulation. 2003; 107: 1308–1314.LinkGoogle Scholar14 Lemstrom KB, Krebs R, Nykanen AI, et al. Vascular endothelial growth factor enhances cardiac allograft arteriosclerosis. Circulation. 2002; 105: 2524–2530.LinkGoogle Scholar15 Moulton KS, Heller E, Konerding MA, et al. Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation. 1999; 99: 1726–1732.CrossrefMedlineGoogle Scholar16 Tanaka H, Sukhova G, Libby P. Interaction of the allogeneic state and hypercholesterolemia in arterial lesion formation in experimental cardiac allografts. Arterioscler Thromb. 1994; 14: 734–745.CrossrefMedlineGoogle Scholar17 Freeman MR, Schneck FX, Gagnon ML, et al. Peripheral blood T lymphocytes and lymphocytes infiltrating human cancers express vascular endothelial growth factor: a potential role for T cells in angiogenesis. Cancer Res. 1995; 55: 4140–4145.MedlineGoogle Scholar18 Zhao XM, Hu Y, Miller GG, et al. Association of thrombospondin-1 and cardiac allograft vasculopathy in human cardiac allografts. Circulation. 2001; 103: 525–531.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Stehlik J, Armstrong B, Baran D, Bridges N, Chandraker A, Gordon R, De Marco T, Givertz M, Heroux A, Iklé D, Hunt J, Kfoury A, Madsen J, Morrison Y, Feller E, Pinney S, Tripathi S, Heeger P and Starling R (2019) Early immune biomarkers and intermediate‐term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation‐18, American Journal of Transplantation, 10.1111/ajt.15218, 19:5, (1518-1528), Online publication date: 1-May-2019. Jin Y, Valenzuela N, Zhang X, Rozengurt E and Reed E (2018) HLA Class II–Triggered Signaling Cascades Cause Endothelial Cell Proliferation and Migration: Relevance to Antibody-Mediated Transplant Rejection, The Journal of Immunology, 10.4049/jimmunol.1701259, 200:7, (2372-2390), Online publication date: 1-Apr-2018. Nie X, Randolph G, Elvington A, Bandara N, Zheleznyak A, Gropler R, Woodard P and Lapi S (2016) Imaging of hypoxia in mouse atherosclerotic plaques with 64Cu-ATSM, Nuclear Medicine and Biology, 10.1016/j.nucmedbio.2016.05.011, 43:9, (534-542), Online publication date: 1-Sep-2016. Loupy A, Vernerey D, Viglietti D, Aubert O, Duong Van Huyen J, Empana J, Bruneval P, Glotz D, Legendre C, Jouven X and Lefaucheur C (2015) Determinants and Outcomes of Accelerated Arteriosclerosis, Circulation Research, 117:5, (470-482), Online publication date: 14-Aug-2015. Valenzuela N and Reed E (2015) Antibodies to HLA Molecules Mimic Agonistic Stimulation to Trigger Vascular Cell Changes and Induce Allograft Injury, Current Transplantation Reports, 10.1007/s40472-015-0065-6, 2:3, (222-232), Online publication date: 1-Sep-2015. Tsai E and Reed E (2014) MHC class I signaling: new functional perspectives for an old molecule, Tissue Antigens, 10.1111/tan.12381, 83:6, (375-381), Online publication date: 1-Jun-2014. Peter S, Hulme O, Deuse T, Vrtovec B, Fearon W, Hunt S and Haddad F (2013) ST-Elevation Myocardial Infarction Following Heart Transplantation as an Unusual Presentation of Coronary Allograft Vasculopathy: A Case Report, Transplantation Proceedings, 10.1016/j.transproceed.2012.08.021, 45:2, (787-791), Online publication date: 1-Mar-2013. Daly K, Seifert M, Chandraker A, Zurakowski D, Nohria A, Givertz M, Karumanchi S and Briscoe D (2013) VEGF-C, VEGF-A and related angiogenesis factors as biomarkers of allograft vasculopathy in cardiac transplant recipients, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2012.09.030, 32:1, (120-128), Online publication date: 1-Jan-2013. Gardner D, Chen S, Glenn D and Ni W (2011) Vitamin D and the Cardiovascular System Vitamin D, 10.1016/B978-0-12-381978-9.10031-9, (541-563), . Egan C, Caporali F, Capecchi P, Lazzerini P, Pasini F and Sorrentino V (2010) Levels of circulating CXCR4-positive cells are decreased and negatively correlated with risk factors in cardiac transplant recipients, Heart and Vessels, 10.1007/s00380-010-0053-9, 26:3, (258-266), Online publication date: 1-May-2011. Soman P and McNamara D (2010) Surveillance for post-transplant coronary artery vasculopathy: Shifting gears from diagnosis to prognosis, Journal of Nuclear Cardiology, 10.1007/s12350-010-9198-2, 17:2, (172-174), Online publication date: 1-Apr-2010. Mas V, Archer K, Scian M and Maluf D (2014) Molecular pathways involved in loss of graft function in kidney transplant recipients, Expert Review of Molecular Diagnostics, 10.1586/erm.10.6, 10:3, (269-284), Online publication date: 1-Apr-2010. Larose E, Behrendt D, Kinlay S, Selwyn A, Ganz P and Fang J (2009) Endothelin-1 Is a Key Mediator of Coronary Vasoconstriction in Patients With Transplant Coronary Arteriosclerosis, Circulation: Heart Failure, 2:5, (409-416), Online publication date: 1-Sep-2009. Raemer P, Haemmerling S, Giese T, Canaday D, Katus H, Dengler T and Shankar S (2009) Endothelial Progenitor Cells Possess Monocyte-like Antigen-presenting and T-cell-Co-stimulatory Capacity, Transplantation, 10.1097/TP.0b013e3181957308, 87:3, (340-349), Online publication date: 15-Feb-2009. Maluf D, Mas V, Archer K, Yanek K, Gibney E, King A, Cotterell A, Fisher R and Posner M (2008) Molecular Pathways Involved in Loss of Kidney Graft Function with Tubular Atrophy and Interstitial Fibrosis, Molecular Medicine, 10.2119/2007-00111.Maluf, 14:5-6, (276-285), Online publication date: 1-May-2008. Thaunat O, Louedec L, Graff-Dubois S, Dai J, Groyer E, Yacoub-Youssef H, Mandet C, Bruneval P, Kaveri S, Caligiuri G, Germain S, Michel J and Nicoletti A (2008) Antiangiogenic Treatment Prevents Adventitial Constrictive Remodeling in Graft Arteriosclerosis, Transplantation, 10.1097/TP.0b013e318160500a, 85:2, (281-289), Online publication date: 27-Jan-2008. Contreras A, Dormond O, Edelbauer M, Calzadilla K, Hoerning A, Pal S and Briscoe D (2008) mTOR—Understanding the Clinical Effects, Transplantation Proceedings, 10.1016/j.transproceed.2008.10.011, 40:10, (S9-S12), Online publication date: 1-Dec-2008. Jin Y, Korin Y, Zhang X, Jindra P, Rozengurt E and Reed E (2007) RNA Interference Elucidates the Role of Focal Adhesion Kinase in HLA Class I-Mediated Focal Adhesion Complex Formation and Proliferation in Human Endothelial Cells, The Journal of Immunology, 10.4049/jimmunol.178.12.7911, 178:12, (7911-7922), Online publication date: 15-Jun-2007. Montet X, Figueiredo J, Alencar H, Ntziachristos V, Mahmood U and Weissleder R (2007) Tomographic Fluorescence Imaging of Tumor Vascular Volume in Mice, Radiology, 10.1148/radiol.2423052065, 242:3, (751-758), Online publication date: 1-Mar-2007. Reinders M, Rabelink T and Briscoe D (2006) Angiogenesis and Endothelial Cell Repair in Renal Disease and Allograft Rejection, Journal of the American Society of Nephrology, 10.1681/ASN.2005121250, 17:4, (932-942), Online publication date: 1-Apr-2006. Danese S, Sans M, de la Motte C, Graziani C, West G, Phillips M, Pola R, Rutella S, Willis J, Gasbarrini A and Fiocchi C (2006) Angiogenesis as a Novel Component of Inflammatory Bowel Disease Pathogenesis, Gastroenterology, 10.1053/j.gastro.2006.03.054, 130:7, (2060-2073), Online publication date: 1-Jun-2006. Skaro A, Liwski R, O'Neill J, Vessie E, Zhou J, Hirsch G and Lee T (2005) Impairment of recipient cytolytic activity attenuates allograft vasculopathy, Transplant Immunology, 10.1016/j.trim.2004.12.003, 14:1, (27-35), Online publication date: 1-Mar-2005. Cacicedo J, Yagihashi N, Keaney J, Ruderman N and Ido Y (2004) AMPK inhibits fatty acid-induced increases in NF-κB transactivation in cultured human umbilical vein endothelial cells, Biochemical and Biophysical Research Communications, 10.1016/j.bbrc.2004.09.177, 324:4, (1204-1209), Online publication date: 1-Nov-2004. Mitchell R (2004) Allograft arteriopathy, Cardiovascular Pathology, 10.1016/S1054-8807(03)00108-X, 13:1, (33-40), Online publication date: 1-Jan-2004. Pinney S and Mancini D (2004) Cardiac allograft vasculopathy: advances in understanding its pathophysiology, prevention, and treatment, Current Opinion in Cardiology, 10.1097/00001573-200403000-00019, 19:2, (170-176), Online publication date: 1-Mar-2004. Raines E (2004) PDGF and cardiovascular disease, Cytokine & Growth Factor Reviews, 10.1016/j.cytogfr.2004.03.004, 15:4, (237-254), Online publication date: 1-Aug-2004. Vos I, Joles J and Rabelink T (2004) The role of nitric oxide in renal transplantation, Seminars in Nephrology, 10.1016/j.semnephrol.2004.04.009, 24:4, (379-388), Online publication date: 1-Jul-2004. Hu Y, Davison F, Zhang Z and Xu Q (2003) Endothelial Replacement and Angiogenesis in Arteriosclerotic Lesions of Allografts Are Contributed by Circulating Progenitor Cells, Circulation, 108:25, (3122-3127), Online publication date: 23-Dec-2003. Sgambat K, Clauss S and Moudgil A (2020) Circulating de novo Donor Specific Antibodies and Carotid Intima-media Thickness in Pediatric Kidney Transplant Recipients, A Pilot Study, Frontiers in Pediatrics, 10.3389/fped.2020.00017, 8 March 11, 2003Vol 107, Issue 9 Advertisement Article InformationMetrics https://doi.org/10.1161/01.CIR.0000059744.64373.08PMID: 12628940 Originally publishedMarch 11, 2003 KeywordsarteriosclerosisangiogenesistransplantationEditorialsinflammationPDF download Advertisement
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