The role of mast cells in atherosclerosis

Summary

Rupture of an atherosclerotic plaque is the major underlying cause of adverse cardiovascular events such as myocardial infarction or stroke. Therapeutic interventions should therefore be directed towards inhibiting growth of atherosclerotic lesions as well as towards prevention of lesion destabilization. Interestingly, the presence of mast cells has been demonstrated in both murine and human plaques, and multiple interventional murine studies have pointed out a direct role for mast cells in early and late stages of atherosclerosis. Moreover, it has recently been described that activated lesional mast cells correlate with major cardiovascular events in patients suffering from cardiovascular disease.

This review focuses on the effect of different mast cell derived mediators in atherogenesis and in late stage plaque destabilization. Also, possible ligands for mast cell activation in the context of atherosclerosis are discussed. Finally, we will elaborate on the predictive value of mast cells, together with therapeutic implications, in cardiovascular disease.

Zusammenfassung

Die Ruptur einer atherosklerotischen Plaque ist der wichtigste Auslöser unerwünschter kardiovaskulärer Ereignisse wie Myokardinfarkt oder Schlaganfall. Daher sollten therapeutische Interventionen auf die Inhibition des Wachstums atherosklerotischer Läsionen zielen und außerdem der Destabilisierung der Läsionen vorbeugen. Interessant ist, dass bei Nagern und auch beim Menschen Mastzellen in Plaques nachgewiesen wurden. Zahlreiche Interventionsstudien an Nagern wiesen auf eine direkte Rolle der Mastzellen im Frühund Spätstadium der Atherosklerose hin. Darüber hinaus wurde kürzlich beschrieben, dass aktivierte läsionale Mastzellen bei Patienten mit Herz-Kreislauf-Krankheiten mit größeren kardiovaskulären Ereignissen in Zusammenhang stehen.

In dieser Übersicht liegt der Fokus auf dem Effekt der von Mastzellen freigesetzten Zytokine bei der Atherogenese und Destabilisierung der Plaques im Spätstadium. Daneben werden mögliche Liganden für die Mastzellaktivierung im Kontext der Atherosklerose diskutiert. Schließlich befassen wir uns noch mit der prognostischen Bedeutung der Mastzellen sowie den therapeutischen Konsequenzen bei Herz-Kreislauf-Krankheiten.

Keywords

Mast cells - atherosclerosis - plaque instability - proteases - therapy

Schlüsselwörter

Mastzellen - Atherosklerose - Plaqueinstabilität - Proteasen - Therapie

• References

• 1 Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol 2004; 04: 787-799.
• 2 Grimbaldeston MA, Chen CC, Piliponsky AM. et al. Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 2005; 167: 835-848.
• 3 Kitamura Y, Go S, Hatanaka K. Decrease of mast cells in W/Wv mice and their increase by bone marrow transplantation. Blood 1978; 52: 447-452.
• 4 Lindstedt KA, Mäyränpää MI, Kovanen PT. Mast cells in vulnerable atherosclerotic plaques--a view to a kill. J Cell Mol Med 2007; 11: 739-758.
• 5 Constantinides P. Mast cells and susceptibility to experimental atherosclerosis. Science 1953; 117: 505-506.
• 6 Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014; 114: 1852-1866.
• 7 Willems S, Vink A, Bot I. et al. Mast cells in human carotid atherosclerotic plaques are associated with intraplaque microvessel density and the occurrence of future cardiovascular events. Eur Heart J 2013; 34: 3699-3706.
• 8 Kovanen PT. Mast cells in human fatty streaks and atheromas: implications for intimal lipid accumulation. Curr Opin Lipidol 1996; 07: 281-286.
• 9 Kovanen PT. The mast cell--a potential link between inflammation and cellular cholesterol deposition in atherogenesis. Eur Heart J 1993; 14 Suppl K: 105-117.
• 10 Lee M, Sommerhoff CP, von Eckardstein A. et al. Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol. Arterioscler Thromb Vasc Biol 2002; 22: 2086-2091.
• 11 Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature 1998; 394: 894-897.
• 12 Combadière C, Potteaux S, Rodero M. et al. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo) monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation 2008; 117: 1649-1657.
• 13 De Filippo K. et al. Mast cell and macrophage chemokines CXCL1/CXCL2 control the early stage of neutrophil recruitment during tissue inflammation. Blood 2013; 121: 4930-4937.
• 14 De Jager SCA. et al. Leukocyte-specific CCL3 deficiency inhibits atherosclerotic lesion development by affecting neutrophil accumulation. Arterioscler Thromb Vasc Biol 2013; 33: e75-e83.
• 15 Döring Y, Soehnlein O, Weber C. Neutrophils cast NETs in atherosclerosis: employing peptidylarginine deiminase as a therapeutic target. Circ Res 2014; 114: 931-934.
• 16 Drechsler M, Megens RT, van Zandvoort M. et al. Hyperlipidemia-triggered neutrophilia promotes early atherosclerosis. Circulation 2010; 122: 1837-1845.
• 17 Bot I, Wezel A, Lagraauw HM. et al. Mast cell mediated neutrophil influx enhances plaque progression. Cardiovasc Res 2014; 103 (Suppl. 01) S5.
• 18 Huang M, Pang X, Letourneau R. et al. Acute stress induces cardiac mast cell activation and histamine release, effects that are increased in Apolipoprotein E knockout mice. Cardiovasc Res 2002; 55: 150-160.
• 19 Bot I, de Jager SC, Zernecke A. et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation 2007; 115: 2516-2525.
• 20 Sun J, Sukhova GK, Wolters PJ. et al. Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med 2007; 13: 719-724.
• 21 Heikkilä HM, Trosien J, Metso J. et al. Mast cells promote atherosclerosis by inducing both an atherogenic lipid profile and vascular inflammation. J Cell Biochem 2010; 109: 615-623.
• 22 Virmani R, Kolodgie FD, Burke AP. et al. Lessons from sudden coronary death: a comprehensive morphological classification scheme for atherosclerotic lesions. Arterioscler Thromb Vasc Biol 2000; 20: 1262-1275.
• 23 Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of activated mast cells at the site of coronary atheromatous erosion or rupture in myocardial infarction. Circulation 1995; 92: 1084-1088.
• 24 Kaartinen M, Penttilä A, Kovanen PT. Mast cells of two types differing in neutral protease composition in the human aortic intima. Demonstration of tryptase and tryptase/chymase-containing mast cells in normal intimas, fatty streaks, and the shoulder region of atheromas. Arterioscler Thromb 1994; 14: 966-972.
• 25 Dai H, Korthuis RJ. Mast cell proteases and inflammation. Drug Discov Today Dis Models 2011; 08: 47-55.
• 26 Caughey GH, Raymond WW, Wolters PJ. Angiotensin II generation by mast cell alpha-and betachymases. Biochim Biophys Acta 2000; 1480: 245-257.
• 27 Johnson JL, Jackson CL, Angelini GD, George SJ. Activation of matrix-degrading metalloproteinases by mast cell proteases in atherosclerotic plaques. Arterioscler Thromb Vasc Biol 1998; 18: 1707-1715.
• 28 Leskinen MJ, Heikkilä HM, Speer MY. et al. Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling. Exp Cell Res 2006; 312: 1289-1298.
• 29 Heikkilä HM, Lätti S, Leskinen MJ. et al. Activated mast cells induce endothelial cell apoptosis by a combined action of chymase and tumor necrosis factor-alpha. Arterioscler Thromb Vasc Biol 2008; 28: 309-314.
• 30 Tani K, Ogushi F, Shimizu T, Sone S. Protease-induced leukocyte chemotaxis and activation: roles in host defense and inflammation. J Med Invest 2001; 48: 133-141.
• 31 Bot I, Bot M, van Heiningen SH. et al. Mast cell chymase inhibition reduces atherosclerotic plaque progression and improves plaque stability in ApoE-/mice. Cardiovasc Res 2011; 89: 244-52.
• 32 Zhi X, Xu C, Zhang H. et al. Tryptase promotes atherosclerotic plaque haemorrhage in ApoE-/- mice. PLoS One 2013; 08: e60960.
• 33 Lappalainen H, Laine P, Pentikäinen MO. et al. Mast cells in neovascularized human coronary plaques store and secrete basic fibroblast growth factor, a potent angiogenic mediator. Arterioscler Thromb Vasc Biol 2004; 24: 1880-1885.
• 34 Lu C, Diehl SA, Noubade R. et al. Endothelial histamine H1 receptor signaling reduces blood-brain barrier permeability and susceptibility to autoimmune encephalomyelitis. Proc Natl Acad Sci 2010; 107: 18967-18972.
• 35 Rozenberg I, Sluka SH, Rohrer L. et al. Histamine H1 receptor promotes atherosclerotic lesion formation by increasing vascular permeability for low-density lipoproteins. Arterioscler Thromb Vasc Biol 2010; 30: 923-930.
• 36 Wang J, Cheng X, Xiang MX. et al. IgE stimulates human and mouse arterial cell apoptosis and cytokine expression and promotes atherogenesis in Apoe-/mice. J Clin Invest 2011; 121: 3564-3577.
• 37 Speidl WS, Kastl SP, Hutter R. et al. The complement component C5a is present in human coronary lesions in vivo and induces the expression of MMP-1 and MMP-9 in human macrophages in vitro. FASEB J 2011; 25: 35-44.
• 38 De Vries MR, Wezel A, Schepers A. et al. Complement factor C5a as mast cell activator mediates vascular remodelling in vein graft disease. Cardiovasc Res 2013; 97: 311-320.
• 39 Wezel A, de Vries MR, Lagraauw HM. et al. Complement factor C5a induces atherosclerotic plaque disruptions. J Cell Mol Med 2014; 18: 2020-2030.
• 40 Sandig H, Bulfone-Paus S. TLR signaling in mast cells: common and unique features. Front Immunol 2012; 03: 185.
• 41 Hollestelle SC, De Vries MR, Van Keulen JK. et al. Toll-like receptor 4 is involved in outward arterial remodeling. Circulation 2004; 109: 393-398.
• 42 Den Dekker WK, Tempel D, Bot I. et al. Mast cells induce vascular smooth muscle cell apoptosis via a toll-like receptor 4 activation pathway. Arterioscler Thromb Vasc Biol 2012; 32: 1960-1969.
• 43 Willems S, van der Velden D, Quax PH. et al. Circulating immunoglobulins are not associated with intraplaque mast cell number and othervulnerable plaque characteristics in patients with carotid artery stenosis. PLoS One 2014; 09: e88984.
• 44 Lappalainen J, Lindstedt KA, Oksjoki R, Kovanen PT. OxLDL-IgG immune complexes induce expression and secretion of proatherogenic cytokines by cultured human mast cells. Atherosclerosis 2011; 214: 357-363.
• 45 Bot M, de Jager SC, MacAleese L. et al. Lysophosphatidic acid triggers mast cell-driven atherosclerotic plaque destabilization by increasing vascular inflammation. J Lipid Res 2013; 54: 1265-1274.
• 46 Laine P, Naukkarinen A, Heikkilä L. et al. Adventitial mast cells connect with sensory nerve fibers in atherosclerotic coronary arteries. Circulation 2000; 101: 1665-1669.
• 47 Bot I, de Jager SC, Bot M. et al. The neuropeptide substance P mediates adventitial mast cell activation and induces intraplaque hemorrhage in advanced atherosclerosis. Circ Res 2010; 106: 89-92.
• 48 Lagraauw HM, Westra MM, Bot M. et al. Vascular neuropeptide Y contributes to atherosclerotic plaque progression and perivascular mast cell activation. Atherosclerosis 2014; 235: 196-203.
• 49 Kounis NG. Coronary hypersensitivity disorder: the Kounis syndrome. Clin Ther 2013; 35: 563-571.
• 50 Undas A, Cieœla-Dul M. Dr¹¿kiewicz T et al. Association between atopic diseases and venous thromboembolism: a case-control study in patients aged 45 years or less. J Thromb Haemost 2011; 09: 870-873.
• 51 Knoflach M, Kiechl S, Mayr A. et al. Allergic rhinitis, asthma, and atherosclerosis in the Bruneck and ARMY studies. Arch Intern Med 2005; 165: 2521-2526.
• 52 Skaaby T, Husemoen LL, Thuesen BH. et al. The association of atopy with incidence of ischemic heart disease, stroke, and diabetes. Endocrine. 2014 Epub ahead of print.
• 53 Deliargyris EN, Upadhya B, Sane DC. et al. Mast cell tryptase: a new biomarker in patients with stable coronary artery disease. Atherosclerosis 2005; 178: 381-386.
• 54 Van Haelst PL, Timmer JR, Crijns HJ. et al. No long-lasting or intermittent mast cell activation in acute coronary syndromes. Int J Cardiol 2001; 78: 75-80.
• 55 Kovanen PT, Mänttäri M, Palosuo T. et al. Prediction of myocardial infarction in dyslipidemic men by elevated levels of immunoglobulin classes A, E, and G, but not M. Arch Intern Med 1998; 158: 1434-1439.
• 56 Mayer FJ, Gruenberger D, Schillinger M. et al. Prognostic value of neutrophils in patients with asymptomatic carotid artery disease. Atherosclerosis 2013; 231: 274-280.
• 57 Matsumura T, Taketa K, Motoshima H. et al. Association between circulating leukocyte subtype counts and carotid intima-media thickness in Japanese subjects with type 2 diabetes. Cardiovasc Diabetol 2013; 27; 12: 177.
• 58 Gabbasov ZA, Kozlov SG, Lyakishev AA. et al. Polymorphonuclear blood leukocytes and restenosis after intracoronary implantation of drug-eluting stents. Can J Physiol Pharmacol 2009; 87: 130-136.
• 59 Holmes Jr DR, Savage M, LaBlanche JM. et al. Results of Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. Circulation 2002; 106: 1243-1250.