Abstract
Inflammation is considered an important aspect in the development of atherosclerosis. Genetic manipulations of animal models susceptible to atherosclerosis have unraveled the contribution of various inflammatory pathways implicated in the development of atherosclerosis. These inflammatory pathways not only lead to the recruitment and entry of inflammatory cells into the arterial wall, they also modify the morphology and composition of atherosclerotic plaques. Certain inflammatory pathways, such as P-selectin, intercellular adhesion molecule-1, and vascular cell adhesion molecule-1, appear to play an important role in lesion initiation, whereas others, such as interleukin-10 and CD40/CD40 ligand, seem to contribute to lesion progression and morphologic changes. An understanding of these pathways will allow the development of new strategies in the management of atherosclerosis. This review provides a roadmap for better utilization of these models in atherosclerosis research.
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References and Recommended Reading
Lawn R, Wade D, Hammer R, et al.: Atherogenesis in transgenic mice expressing human apolipoprotein(a). Nature 1992, 360:670–672.
Tenger C, Zhou X: Apolipoprotein E modulates immune activation by acting on the antigen-presenting cell. Immunology 2003, 109:392–397.
Calara F, Silvestre M, Casanada F, et al.: Spontaneous plaque rupture and secondary thrombosis in apolipoprotein E-deficient and LDL receptor-deficient mice. J Pathol 2001, 195:257–263.
Masucci-Magoulas L, Goldberg I, Bisgaier C, et al.: A mouse model with features of familial combined hyperlipidemia. Science 1997, 275:391–394.
Bannykh S, Witztum J, Bergmark C: Mechanical aortic injury in apoE-deficient mice as a model for development of atherosclerosis: demonstration of leukocyte rolling early after injury. Ultrastructural Pathol 2002, 26:251–260.
von der Thüsen J, van Berkel T, Biessen E: Induction of rapid atherogenesis by perivascular carotid collar placement in apolipoprotein E-deficient and low-density lipoprotein receptor-deficient mice. Circulation 2001, 103:1164–1170.
Grimsditch DC, Penfold S, Latcham J, et al.: C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile. Atherosclerosis 2000, 151:389–397.
Shi W, Wang NJ, Shih DM, et al.: Determinants of atherosclerosis susceptibility in the C3H and C57BL/6 mouse model: evidence for involvement of endothelial cells but not blood cells or cholesterol metabolism. Circ Res 2000, 86:1078–1084.
Tabibiazar R, Wagner RA, Spin JM, et al.: Mouse strain-specific differences in vascular wall gene expression and their relationship to vascular disease. Arterioscler Thromb 2005, 25:302–308.
Johnson R, Chapman S, Dong Z, et al.: Absence of P-selectin delays fatty streak formation in mice. J Clin Invest 1997, 99:1037–1043.
Dong Z, Brown A, Wagner D: Prominent role of P-selectin in the development of advanced atherosclerosis in ApoE-deficient mice. Circulation 2000, 101:2290–2295.
Nageh M, Sandberg E, Marotti K, et al.: Deficiency of inflammatory cell adhesion molecules protects against atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1997, 17:1517–1520.
Molenaar T, Twisk J, de Haas S, et al.: P-selectin as a candidate target in atherosclerosis. Biochem Pharmacol 2003, 66:859–866.
Kumar A, Hoover J, Simmons C, et al.: Remodeling and neointimal formation in the carotid artery of normal and P-selectin-deficient mice. Circulation 1997, 96:4333–4342.
Manka D, Collins R, Ley K, et al.: Absence of P-selectin, but not intercellular adhesion molecule-1, attenuates neointimal growth after arterial injury in apolipoprotein e-deficient mice. Circulation 2001, 103:1000–1005.
Hayashi S, Watanabe N, Nakazawa K, et al.: Roles of P-selectin in inflammation, neointimal formation, and vascular remodeling in balloon-injured rat carotid arteries. Circulation 2000, 102:1710–1717.
Molenaar T, Appeldoorn C, de Haas S, et al.: Specific inhibition of P-selectin-mediated cell adhesion by phage display-derived peptide antagonists. Blood 2002, 100:3570–3577.
Iiyama K, Hajra L, Iiyama M, 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, 85:199–207.
Collins R, Velji R, Guevara N, et al.: P-Selectin or intercellular adhesion molecule (ICAM)-1 deficiency substantially protects against atherosclerosis in apolipoprotein E-deficient mice. J Exp Med 2000, 191:189–194.
Patel S, Thiagarajan R, Willerson J, Yeh E: Inhibition of alpha4 integrin and ICAM-1 markedly attenuate macrophage homing to atherosclerotic plaques in ApoE-deficient mice. Circulation 1998, 97:75–81.
Bourdillon M, Poston R, Covacho C, et al.: ICAM-1 deficiency reduces atherosclerotic lesions in double-knockout mice (ApoE(-/-)/ICAM-1(-/-)) fed a fat or a chow diet. Arterioscler Thromb 2000, 20:2630–2635.
Cybulsky M, Iiyama K, Li H, et al.: A major role for VCAM-1, but not ICAM-1, in early atherosclerosis. J Clin Invest 2001, 107:1255–1262.
Elices M, Osborn L, Takada Y, et al.: VCAM-1 on activated endothelium interacts with the leukocyte integrin VLA-4 at a site distinct from the VLA-4/fibronectin binding site. Cell 1990, 60:577–584.
Li H, Cybulsky M, Gimbrone M, Libby P: An atherogenic diet rapidly induces VCAM-1, a cytokine-regulatable mononuclear leukocyte adhesion molecule, in rabbit aortic endothelium. Arterioscler Thromb 1993, 13:197–204.
Sakai A, Kume N, Nishi E, et al.: P-selectin and vascular cell adhesion molecule-1 are focally expressed in aortas of hypercholesterolemic rabbits before intimal accumulation of macrophages and T lymphocytes. Arterioscler Thromb Vasc Biol 1997, 17:310–316.
Nakashima Y, Raines E, Plump A, et al.: Upregulation of VCAM-1 and ICAM-1 at atherosclerosis-prone sites on the endothelium in the ApoE-deficient mouse. Arterioscler Thromb Vasc Biol 1998, 18:842–851.
Gurtner G, Davis V, Li H, et al.: Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev 1995, 9:1–14.
Koni P, Joshi S, Temann U, et al.: Conditional vascular cell adhesion molecule 1 deletion in mice: impaired lymphocyte migration to bone marrow. J Exp Med 2001, 193:741–754.
Dansky H, Barlow C, Lominska C, et al.: Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler Thromb 2001, 21:1662–1667.
Shih P, Brennan M, Vora D, et al.: Blocking very late antigen-4 integrin decreases leukocyte entry and fatty streak formation in mice fed an atherogenic diet. Circ Res 1999, 84:345–351.
Bavendiek U, Zirlik A, LaClair S, et al.: Atherogenesis in mice does not require CD40 ligand from bone marrow-derived cells. Arterioscler Thromb 2005, 25:1244–1249.
Mach F, Schönbeck U, Sukhova G, et al.: Reduction of atherosclerosis in mice by inhibition of CD40 signalling. Nature 1998, 394:200–203.
Schönbeck U, Sukhova G, Shimizu K, et al.: Inhibition of CD40 signaling limits evolution of established atherosclerosis in mice. Proc Natl Acad Sci U S A 2000, 97:7458–7463.
Lutgens E, Gorelik L, Daemen M, et al.: Requirement for CD154 in the progression of atherosclerosis. Nat Med 1999, 5:1313–1316.
Qiao J, Tripathi J, Mishra N, et al.: Role of macrophage colony-stimulating factor in atherosclerosis: studies of osteopetrotic mice. Am J Pathol 1997, 150:1687–1699.
Smith J, Trogan E, Ginsberg M, et al.: Decreased atherosclerosis in mice deficient in both macrophage colony-stimulating factor (op) and apolipoprotein E. Proc Natl Acad Sci U S A 1995, 92:8264–8268.
Boring L, Gosling J, Chensue S, et al.: Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. J Clin Invest 1997, 100:2552–2561.
Lu B, Rutledge B, Gu L, et al.: Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998, 187:601–608.
Takeya M, Yoshimura T, Leonard E, Takahashi K: Detection of monocyte chemoattractant protein-1 in human atherosclerotic lesions by an anti-monocyte chemoattractant protein-1 monoclonal antibody. Hum Pathol 1993, 24:534–539.
Clinton S, Libby P: Cytokines and growth factors in atherogenesis. Arch Pathol Lab Med 1992, 116:1292–1300.
Yu X, Dluz S, Graves D, et al.: elevated expression of monocyte chemoattractant protein 1 by vascular smooth muscle cells in hypercholesterolemic primates. Proc Natl Acad Sci U S A 1992, 89:6953–6957.
Kuziel WA, Morgan SJ, Dawson TC, et al.: Severe reduction in leukocyte adhesion and monocyte extravasation in mice deficient in CC chemokine receptor 2. Proc Natl Acad Sci U S A 1997, 94:12053–12058.
Reckless J, Rubin E, Verstuyft J, et al.: Monocyte chemoattractant protein-1 but not tumor necrosis factor-alpha is correlated with monocyte infiltration in mouse lipid lesions. Circulation 1999, 99:2310–2316.
Gu L, Okada Y, Clinton S, et al.: Absence of monocyte chemoattractant protein-1 reduces atherosclerosis in low density lipoprotein receptor-deficient mice. Mol Cell 1998, 2:275–281.
Gosling J, Slaymaker S, Gu L, et al.: MCP-1 deficiency reduces susceptibility to atherosclerosis in mice that overexpress human apolipoprotein B. J Clin Invest 1999, 103:773–778.
Dawson T, Kuziel W, Osahar T, Maeda N: Absence of CC chemokine receptor-2 reduces atherosclerosis in apolipoprotein E-deficient mice. Atherosclerosis 1999, 143:205–211.
Boring L, Gosling J, Cleary M, Charo I: Decreased lesion formation in CCR2-/-mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998, 394:894–897.
Namiki M, Kawashima S, Yamashita T, et al.: Local over-expression of monocyte chemoattractant protein-1 at vessel wall induces infiltration of macrophages and formation of atherosclerotic lesion: synergism with hypercholesterolemia. Arterioscler Thromb 2002, 22:115–120.
Ni W, Egashira K, Kitamoto S, et al.: New anti-monocyte chemoattractant protein-1 gene therapy attenuates atherosclerosis in apolipoprotein E-knockout mice. Circulation 2001, 103:2096–2101.
Inoue, S, Egashira K, Ni W, et al.: Anti-monocyte chemoattractant protein-1 gene therapy limits progression and destabilization of established atherosclerosis in apolipoprotein E-knockout mice. Circulation 2002, 106:2700–2706.
Usui M, Egashira K, Ohtani K, et al.: Anti-monocyte chemoattractant protein-1 gene therapy inhibits restenotic changes (neointimal hyperplasia) after balloon injury in rats and monkeys. FASEB J 2002, 16:1838–1840.
Kuziel W, Dawson T, Quinones M, et al.: CCR5 deficiency is not protective in the early stages of atherogenesis in apoE knockout mice. Atherosclerosis 2003, 167:25–32.
Braunersreuther V, Zernecke A, Arnaud C, et al.: CCR5 but not CCR1 deficiency reduces development of diet-induced atherosclerosis in mice. Arterioscler Thromb Vasc Biol 2007, 27:373–379.
Zernecke A, Liehn E, Gao J, et al.: Deficiency in CCR5 but not CCR1 protects against neointima formation in atherosclerosis-prone mice: involvement of IL-10. Blood 2006, 107:4240–4243.
van Wanrooij EJ, Happe H, Hauer AD, et al.: HIV entry inhibitor TAK-779 attenuates atherogenesis in low-density lipoprotein receptor-deficient mice. Arterioscler Thromb Vasc Biol 2005, 25:2642–2647.
Wilcox JN, Nelken NA, Coughlin SR, et al.: Local expression of inflammatory cytokines in human atherosclerotic plaques. J Atheroscler Thromb 1994, 1(Suppl 1):S10–S13.
Haley KJ, Lilly CM, Yang JH, et al.: Overexpression of eotaxin and the CCR3 receptor in human atherosclerosis: using genomic technology to identify a potential novel pathway of vascular inflammation. Circulation 2000, 102:2185–2189.
Inoue T, Komoda H, Nonaka M, et al.: Interleukin-8 as an independent predictor of long-term clinical outcome in patients with coronary artery disease. Int J Cardiol 2007 [Epub ahead of print].
Boisvert W, Santiago R, Curtiss L, Terkeltaub R: A leukocyte homologue of the IL-8 receptor CXCR-2 mediates the accumulation of macrophages in atherosclerotic lesions of LDL receptor-deficient mice. J Clin Invest 1998, 101:353–363.
Boisvert W, Rose D, Johnson K, et al.: Up-regulated expression of the CXCR2 ligand KC/GRO-alpha in atherosclerotic lesions plays a central role in macrophage accumulation and lesion progression. Am J Pathol 2006, 168:1385–1395.
von der Thüsen J, Kuiper J, van Berkel T, Biessen E: Interleukins in atherosclerosis: molecular pathways and therapeutic potential. Pharmacol Rev 2003, 55:133–166.
Caligiuri G, Rudling M, Ollivier V, et al.: Interleukin-10 deficiency increases atherosclerosis, thrombosis, and low-density lipoproteins in apolipoprotein E knockout mice. Mol Med 2003, 9:10–17.
Pinderski Oslund L, Hedrick C, Olvera T, et al.: Interleukin-10 blocks atherosclerotic events in vitro and in vivo. Arterioscler Thromb Vasc Biol 1999, 19:2847–2853.
Pinderski L, Fischbein M, Subbanagounder G, et al.: Overexpression of interleukin-10 by activated T lymphocytes inhibits atherosclerosis in LDL receptor-deficient mice by altering lymphocyte and macrophage phenotypes. Circ Res 2002, 90:1064–1071.
Von Der Thüsen J, Kuiper J, Fekkes M, et al.: Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr-/-mice. FASEB J 2001, 15:2730–2732.
Whitman S, Ravisankar P, Elam H, Daugherty A: Exogenous interferon-gamma enhances atherosclerosis in apolipoprotein E-/-mice. Am J Pathol 2000, 157:1819–1824.
Tellides G, Tereb D, Kirkiles-Smith N, et al.: Interferon-gamma elicits arteriosclerosis in the absence of leukocytes. Nature 2000, 403:207–211.
Gupta S, Pablo A, Jiang X, et al.: IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. J Clin Invest 1997, 99:2752–2761.
Whitman S, Ravisankar P, Daugherty A: IFN-gamma deficiency exerts gender-specific effects on atherogenesis in apolipoprotein E-/-mice. J Interferon Cytokine Res 2002, 22:661–670.
Koga M, Kai H, Yasukawa H, et al.: Inhibition of progression and stabilization of plaques by postnatal interferon-gamma function blocking in ApoE-knockout mice. Circ Res 2007, 101:348–356.
Davenport P, Tipping PG: The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipoprotein E-deficient mice. Am J Pathol 2003, 163:1117–1125.
Lee T, Yen H, Pan C, Chau L: The role of interleukin 12 in the development of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 1999, 19:734–742.
Hauer A, Uyttenhove C, de Vos P, et al.: Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis. Circulation 2005, 112:1054–1062.
Whitman S, Ravisankar P, Daugherty A: Interleukin-18 enhances atherosclerosis in apolipoprotein E(-/-) mice through release of interferon-gamma. Circ Res 2002, 90:E34–E38.
Mallat Z, Corbaz A, Scoazec A, et al.: Interleukin-18/interleukin-18 binding protein signaling modulates atherosclerotic lesion development and stability. Circ Res 2001, 89:E41–E45.
George J, Mulkins M, Shaish A, et al.: Interleukin (IL)-4 deficiency does not influence fatty streak formation in C57BL/6 mice. Atherosclerosis 2000, 153:403–411.
Huber S, Sakkinen P, Conze D, et al.: Interleukin-6 exacerbates early atherosclerosis in mice. Arterioscler Thromb Vasc Biol 1999, 19:2364–2367.
Bazan J, Bacon K, Hardiman G, et al.: A new class of membrane-bound chemokine with a CX3C motif. Nature 1997, 385:640–644.
Lucas A, Bursill C, Guzik T, et al.: Smooth muscle cells in human atherosclerotic plaques express the fractalkine receptor CX3CR1 and undergo chemotaxis to the CX3C chemokine fractalkine (CX3CL1). Circulation 2003, 108:2498–2504.
Wong B, Wong D, McManus B: Characterization of fractalkine (CX3CL1) and CX3CR1 in human coronary arteries with native atherosclerosis, diabetes mellitus, and transplant vascular disease. Cardiovasc Pathol 2002, 11:332–338.
Teupser D, Pavlides S, Tan M, et al.: Major reduction of atherosclerosis in fractalkine (CX3CL1)-deficient mice is at the brachiocephalic artery, not the aortic root. Proc Natl Acad Sci U S A 2004, 101:17795–17800.
Combadière C, Potteaux S, Gao J, et al.: Decreased atherosclerotic lesion formation in CX3CR1/apolipoprotein E double knockout mice. Circulation 2003, 107:1009–1016.
Lesnik P, Haskell C, Charo I: Decreased atherosclerosis in CX3CR1-/-mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003, 111:333–340.
Berliner J, Navab M, Fogelman A, et al.: Atherosclerosis: basic mechanisms. Oxidation, inflammation, and genetics. Circulation 1995, 91:2488–2496.
Schober A, Zernecke A, Liehn E, et al.: Crucial role of the CCL2/CCR2 axis in neointimal hyperplasia after arterial injury in hyperlipidemic mice involves early monocyte recruitment and CCL2 presentation on platelets. Circ Res 2004, 95:1125–1133.
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Soliman, A., Kee, P. Experimental models investigating the inflammatory basis of atherosclerosis. Curr Atheroscler Rep 10, 260–271 (2008). https://doi.org/10.1007/s11883-008-0040-0
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DOI: https://doi.org/10.1007/s11883-008-0040-0