Mast cells and atherosclerosis

By Guo-Ping Shi, DSc. *

A brief review of recent developments


  1. Mast cells in atherosclerotic lesions
  2. Mast cells and atherosclerosis-associated protease expression
  3. Interactions between mast cells and vascular cells
  4. Proof of concept with animal models
  5. Future perspective
  6. References

1. Mast cells in atherosclerotic lesions
Mast cells are known primarily as essential effector cells in the elicitation of allergic responses. Their appearance in human atherosclerotic lesions was recognized first by Dr. Paris Constantinides more than half a century ago (1). An increase in the number of mast cells in atherosclerotic lesions with variable focal accumulations was later proposed with the progression of human atherosclerosis. Normally, carotid arteries contain only very few mast cells within the adventitia. However, from the earliest stages of atherosclerosis, mast cells are found in the fatty streak and abundantly in close association with lesion macrophages. At a later phase of the disease development, mast cells appear at the shoulder regions of fully formed atheroma prone to erosion or rupture, as well as in the lipid cores of advanced plaques (2,3). Similarly, coronary arteries exhibit greater numbers of mast cells in ruptured plaques than in non-ruptured plaques, while the smallest number of mast cells are found in normal arteries (4,5,6).

An important feature of mast cells is their ability to release the content of their cytoplasmic granules extracellularly upon activation by stimuli such as IgE, complement components, as well as viral and bacterial pathogens. Activated mast cells secrete large amounts of chemotactic molecules, inflammation activators and soluble granule remnants, including cytokines, chemokines, and mediators such as histamine, tryptase, and chymase, which may mediate or modulate atherogenesis (Table 1). In addition, activated mast cells nonspecifically bind to low-density lipoproteins (LDL), which can be phagocytosed by macrophages to form foam cells, a major cellular component of advanced human atherosclerotic lesions (7). Thus, mast cells exhibit a variety of functions that might modulate atherogenesis in vivo.

2. Mast cells and atherosclerosis-associated protease expression
Tryptase and chymase are the most common mast cell specific proteases (Table 1). In addition to degradation of extracellular matrix proteins (ECM) (8), chymase can generate active angiotensin II, TGF-β1 (9), IL-1β (10), and 31-amino acid endothelin (11), which are all essential players in atherogenesis. While chymases proteolytically modify LDL into copper oxidized-LDL to promote foam cell formation (12), tryptases degrade HDL and block its function as an acceptor of cellular cholesterol (13). These enzymes can also activate latent matrix metalloproteinases (MMPs) implicated in plaque remodeling and rupture (14). Increased MMP activities were detected in human carotid atherosclerotic plaques when tissues were treated with a mast cell activator (15), whereas chymase and tryptase inhibitors reduced MMP activities by up to 30%. Upon activation, mast cells also release pro-inflammatory TNF-α to trigger MMP-9 expression and secretion in macrophages (4). Mast cell-derived bFGF may act in a similar manner to induce endothelial cell expression of ECM-degrading proteases, which results in a positive correlation between the number of bFGF-positive mast cells and microvessels in human coronary plaques (16).

3. Interactions between mast cells and vascular cells
Smooth muscle cells (SMCs), endothelial cells (ECs), macrophages, and lymphocytes are probably the major cell types involved in atherogenesis. Mast cells regulate the behavior of SMC most likely through their secreted mediators (Figure 1). For example, histamine, bFGF, TGF-β and PAF released from mast cells can activate SMC surface receptors and accelerate their migration and proliferation (17,18). In contrast, mast cell-derived heparin proteoglycan or heparin glycosaminoglycans inhibit SMC growth efficiently by blocking activation of the extracellular signal-regulated kinases ERK1 and ERK2 (19), and participate in the local regulation of SMC growth in the plaque (20). SMC-derived collagen may help prevent rupture of the atheromatous fibrous caps. However, mast cell-derived chymase inhibits SMC proliferation and collagen synthesis (9), thereby reducing plaque stability. In addition, chymase can induce degradation of focal adhesion kinase and fibronectin, which are mediators of SMC survival and adhesion. Mast cell-released pro-inflammatory cytokines such as TNF-α induce SMC protease expression. The appearance of TNF-α-positive mast cells (21) together with MMP- or cysteine protease cathepsin-positive SMCs and macrophages (22,23) in rupture-prone areas of human coronary atheroma suggest a regulatory role of mast cell mediators in SMC protease expression and activation.

Dr. Pete Kovanen's group has demonstrated that mast cells store and secrete angiogenic bFGF within neovascularized human coronary plaques (16). Activated mast cells containing angiogenic factors preferentially localize around newly formed microvessels in human coronary atheroma (24), suggesting that the interaction between mast cells and ECs can be mediated by mast cell-derived angiogenic factors. Mast cell-derived TNF-α induces the expression of adhesion molecules in ECs (such as ICAM-1, VCAM-1, E-selectin) (25-27) while the secretion of tryptase from mast cells triggers the release of lymphotactic IL-8 by ECs (28,29).

T lymphocytes in atherosclerotic lesions can induce the release of inflammatory cytokines and mast cell chemokines. Mast cells are activated in various T cell-mediated inflammatory processes and reside in close physical proximity to T cells. Indeed, mast cell activation can induce T cell migration, either directly by releasing chemotactic factors or indirectly by inducing the expression of adhesion molecules on ECs (25-27). Upon activation, mast cells release lymphotactin with preferential chemotactic activity on CD8+ T cells (30) or IL-16, a chemoattractant for CD4+ T cells (31) (Figure 1). Mast cells also present antigens to T cells, resulting in their activation in either a MHC class I- or MHC class II-restricted and co-stimulatory molecule-dependent fashion (32,33). In addition to T cells, monocytes and neutrophils can also be recruited by mast cells through secretion of chemokines such as MCP-1 and IL-8. Therefore, mast cells are considered to be a central regulator for different cell types in human atherosclerotic lesions.

4. Proof of concept with animal models
In an apolipoprotein E-deficient (Apoe-/-) mouse model of atherosclerosis, mast cell activation with dinitrophenyl-albumin (DNP) enhanced the size of atherosclerotic lesions in mice by more than 50% (34). In contrast, such an increase of atherosclerosis was absent when DNP-treated animals were further treated with the mast cell stabilizer cromolyn. Consistent with a prior hypothesis (35), degranulated mast cells or the mast cell components histamine and tryptase promoted macrophage apoptosis. Furthermore, increased atherosclerosis in DNP-treated mice was not due to changes in other immune cells, including neutrophils, monocytes, lymphocytes. Thus, activated mast cells appear to have a specific contribution to atherosclerosis independently of other inflammatory cell types.

We used another conventional low-density lipoprotein receptor-null (Ldlr-/-) mouse model for atherosclerosis, and here mast cell-deficient mice directly proved that mast cells play a role in atherosclerosis (36). Mast cell-deficient mice demonstrated a reduction in atherosclerosis by greater than 50% after consumption of an atherogenic diet for 12 to 26 weeks. The numbers of macrophages, T cells, proliferating cells, and apoptotic cells in lesions were also significantly reduced in mast cell-deficient Ldlr-/- mice compared to control Ldlr-/- mice. Using a mast cell reconstitution strategy, we not only restored the atherosclerosis phenotype in mast cell-null mice using wild-type mast cells, but also identified that mast cells contribute to atherosclerosis by releasing pro-inflammatory cytokines IL-6 and IFN-γ to stimulate vascular cell cysteine protease and MMP expression. Both experimental models proved independently the concept that mast cells participate directly in the pathogenesis of atherosclerosis.

5. Future perspective
The release of mediators from mast cell granules is a common pathological event during allergic responses. Consequently, mast cell stabilization has become the main treatment for patients with allergic symptoms. Although it is too early to say that atherosclerosis is an allergic disorder, mast cell stabilization does reduce atherosclerosis in Apoe-/- mice (34). Therefore, it is possible that the mast cell stabilizer cromolyn, a widely used anti-allergic medicine, may become a viable therapy for atherosclerosis and other vascular diseases. We have recently demonstrated that cromolyn prevents aortic elastase perfusion-induced abdominal aortic aneurysms (37). Based on the data from these different animal models, we anticipate that mast cell stabilizers may have applications for other diseases than just allergies.

Activated mast cells contribute not only to allergic and vascular diseases, but also to multiple sclerosis, rheumatoid arthritis, cancer, and probably many other untested diseases (38). One important feature of the mast cell-derived mediators listed in Table 1, is their ability to act uniquely in different diseases, i.e. one mediator may be critical to one disease but not another. For example, mast cell-derived TNF-α is essential in ovalbumin-induced airway hyperresponsiveness in mice (39). However, the same molecule plays a minor role in western diet-induced atherosclerosis (36) and in elastase perfusion-induced abdominal aortic aneurysms (37), as concluded from a TNF-β-deficient (Tnf-/-) mast cell reconstitution protocol in mast cell-deficient mice. Apparently, mast cell reconstitution in mast cell-deficient mice may become an invaluable approach for examination of individual mast cell mediators in different human disease models in future research.

Table 1.  Selected mediators produced by or released from mast cells.


Potential role in atherosclerosis


Pro-inflammatory cytokines:

IL-4, IL-5, IL-6, IL-13, IL-18, IFN-γ, TNF-α

  • chemotaxis
  • endothelial cell activation
  • monocyte recruitement
  • induction of protease expression

6, 21, 40, 41


MCP-1, IL-8, RANTES, eotaxin, leukotriene

  • monocyte recuitement
  • foam cell formation



Tryptase, chymase, angiotensin converting enzyme (ACE), carboxypeptidase, cathepsin G, cysteinyl cathepsins

  • endothelial cell activation
  • fibrinogen cleavage
  • angiotensis II generation
  • lipoprotein degradation
  • tissue/vascular remodelling
  • protease activation

8, 13, 14, 43-46

Hematopoeitic factors:


  • hematopoiesis
  • foam cell formation


Growth factors:


  • angiogensis
  • cellular proliferation

6, 16, 17


  • vasodilation
  • endothelial cell activation

18, 47

Heparin proteoglycan

  • anti-coagulant
  • inhibition of platelet aggregation


Chondroitin sulfate proteoglycan

  • lipoprotein binding


Mast Cells and atherosclerosis

Figure 1: Participation of mast cells and their mediators in atherosclerosis

6. References

  1. Constantinides P. Mast cells and susceptibility to experimental atherosclerosis. Science. 1953;117:505-506.
  2. Jeziorska M, McCollum C, Woolley DE. Mast cell distribution, activation, and phenotype in atherosclerotic lesions of human carotid arteries. J Pathol. 1997;182:115-122.
  3. Cornhill JF, Herderick EE, Stary HC. Topography of human aortic sudanophilic lesions. Monogr Atheroscler. 1990;15:13-19.
  4. Kaartinen M, van der Wal AC, van der Loos CM, Piek JJ, Koch KT, Becker AE, Kovanen PT. Mast cell infiltration in acute coronary syndromes: implications for plaque rupture. J Am Coll Cardiol. 1998;32:606-612.
  5. Laine P, Kaartinen M, Penttila A, Panula P, Paavonen T, Kovanen PT. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 1999;99:361-369.
  6. 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.
  7. Metzler B, Xu Q. The role of mast cells in atherosclerosis. Int Arch Allergy Immunol. 1997; 114:10-14.
  8. Saarinen J, Kalkkinen N, Welgus HG, Kovanen PT. Activation of human interstitial procollagenase through direct cleavage of the Leu83-Thr84 bond by mast cell chymase. J Biol Chem. 1994;269:18134-18140.
  9. Wang Y, Shiota N, Leskinen MJ, Lindstedt KA, Kovanen PT. Mast cell chymase inhibits smooth muscle cell growth and collagen expression in vitro: transforming growth factor-beta1-dependent and -independent effects. Arterioscler Thromb Vasc Biol. 2001;21:1928-1933.
  10. Mizutani H, Schechter N, Lazarus G, Black RA, Kupper TS. Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase. J Exp Med. 1991;174:821-825.
  11. Kido H, Nakano A, Okishima N, Wakabayashi H, Kishi F, Nakaya Y, Yoshizumi M, Tamaki T. Human chymase, an enzyme forming novel bioactive 31-amino acid length endothelins. Biol Chem. 1998;379:885-891.
  12. Paananen K, Kovanen PT. Proteolysis and fusion of low density lipoprotein particles independently strengthen their binding to exocytosed mast cell granules. J Biol Chem. 1994;269:2023-2031.
  13. Lee M, Sommerhoff CP, von Eckardstein A, Zettl F, Fritz H, Kovanen PT. Mast cell tryptase degrades HDL and blocks its function as an acceptor of cellular cholesterol. Arterioscler Thromb Vasc Biol. 2002;22:2086-2091.
  14. 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.
  15. Lindstedt KA, Kokkonen JO, Kovanen PT. Inhibition of copper-mediated oxidation of LDL by rat serosal mast cells. A novel cellular protective mechanism involving proteolysis of the substrate under oxidative stress. Arterioscler Thromb. 1993;13:23-32.
  16. Lappalainen H, Laine P, Pentikainen MO, Sajantila A, Kovanen PT. 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.
  17. Inoue Y, King TE Jr, Tinkle SS, Dockstader K, Newman LS. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders. Am J Pathol. 1996;149:2037-2054.
  18. Toda N. Mechanism of histamine actions in human coronary arteries. Circ Res. 1987;61:280-286.
  19. Kazi M, Lundmark K, Religa P, Gouda I, Larm O, Ray A, Swedenborg J, Hedin U. Inhibition of rat smooth muscle cell adhesion and proliferation by non-anticoagulant heparins. J Cell Physiol. 2002;193:365-372.
  20. Wang Y, Kovanen PT. Heparin proteoglycans released from rat serosal mast cells inhibit proliferation of rat aortic smooth muscle cells in culture. Circ Res. 1999;84:74-83.
  21. Kaartinen M, Penttila A, Kovanen PT. Mast cells in rupture-prone areas of human coronary atheromas produce and store TNF-alpha. Circulation. 1996;94:2787-2792.
  22. Galis ZS, Khatri JJ. Matrix metalloproteinases in vascular remodeling and atherogenesis: the good, the bad, and the ugly. Circ Res. 2002;90:251-262.
  23. Liu J, Sukhova GK, Sun JS, Xu WH, Libby P, Shi GP. Lysosomal cysteine proteases in atherosclerosis. Arterioscler Thromb Vasc Biol. 2004;24:1359-1366.
  24. Kaartinen M, Penttila A, Kovanen PT. Mast cells accompany microvessels in human coronary atheromas: implications for intimal neovascularization and hemorrhage. Atherosclerosis. 1996;123:123-131.
  25. Walsh LJ, Trinchieri G, Waldorf HA, Whitaker D, Murphy GF. Human dermal mast cells contain and release tumor necrosis factor alpha, which induces endothelial leukocyte adhesion molecule 1. Proc Natl Acad Sci U S A. 1991;88:4220-4224.
  26. Meng H, Tonnesen MG, Marchese MJ, Clark RA, Bahou WF, Gruber BL. Mast cells are potent regulators of endothelial cell adhesion molecule ICAM-1 and VCAM-1
  27. Wegner CD, Gundel RH, Reilly P, Haynes N, Letts LG, Rothlein R. Intercellular adhesion molecule-1 (ICAM-1) in the pathogenesis of asthma. Science. 1990;247:456-459.
  28. Moller A, Lippert U, Lessmann D, Kolde G, Hamann K, Welker P, Schadendorf D, Rosenbach T, Luger T, Czarnetzki BM. Human mast cells produce IL-8. J Immunol. 1993;151:3261-3266.
  29. Compton SJ, Cairns JA, Holgate ST, Walls AF. The role of mast cell tryptase in regulating endothelial cell proliferation, cytokine release, and adhesion molecule expression: tryptase induces expression of mRNA for IL-1 beta and IL-8 and stimulates the selective release of IL-8 from human umbilical vein endothelial cells. J Immunol. 1998;161:1939-1946.
  30. Rumsaeng V, Vliagoftis H, Oh CK, Metcalfe DD. Lymphotactin gene expression in mast cells following Fc(epsilon) receptor I aggregation: modulation by TGF-beta, IL-4, dexamethasone, and cyclosporin A. J Immunol. 1997;158:1353-1360.
  31. Rumsaeng V, Cruikshank WW, Foster B, Prussin C, Kirshenbaum AS, Davis TA, Kornfeld H, Center DM, Metcalfe DD. Human mast cells produce the CD4+ T lymphocyte chemoattractant factor, IL-16. J Immunol. 1997;159:2904-2910.
  32. Malaviya R, Twesten NJ, Ross EA, Abraham SN, Pfeifer JD. Mast cells process bacterial Ags through a phagocytic route for class I MHC presentation to T cells. J Immunol. 1996;156:1490-1496.
  33. Mecheri S, David B. Unravelling the mast cell dilemma: culprit or victim of its generosity? Immunol Today. 1997;18:212-215.
  34. Bot I, de Jager SC, Zernecke A, Lindstedt KA, van Berkel TJ, Weber C, Biessen EA. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E-deficient mice. Circulation. 2007;115:2516-2525.
  35. Leskinen MJ, Heikkilä HM, Speer MY, Hakala JK, Laine M, Kovanen PT, Lindstedt KA. Mast cell chymase induces smooth muscle cell apoptosis by disrupting NF-kappaB-mediated survival signaling. Exp Cell Res. 2006;312:1289-1298.
  36. Sun J, Sukhova GK, Wolters PJ, Yang M, Kitamoto S, Libby P, MacFarlane LA, Mallen-St Clair J, Shi GP. Mast cells promote atherosclerosis by releasing proinflammatory cytokines. Nat Med. 2007;13:719-724.
  37. Sun J, Sukhova GK, Yang M, Wolters PJ, MacFarlane LA, Libby P, Sun C, Zhang Y, Liu J, Ennis T, Knispel R, Xiong W, Thompson RW, Baxter TB, Shi GP. Mast cells modulate the pathogenesis of abdominal aortic aneurysms. J Clin Invest. 2007 in press.
  38. Mitch Leslie. Mast cells show their might. Science. 2007;317:614-616.
  39. Nakae S, Ho LH, Yu M, Monteforte R, Iikura M, Suto H, Galli SJ. Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. J Allergy Clin Immunol. 2007;120:48-55.
  40. Kobayashi H, Ishizuka T, Okayama Y. Human mast cells and basophils as sources of cytokines. Clin Exp Allergy. 2000;30:1205-1212.
  41. Huang M, Pang X, Karalis K, Theoharides TC. Stress-induced interleukin-6 release in mice is mast cell-dependent and more pronounced in Apolipoprotein E knockout mice. Cardiovasc Res. 2003;59:241-249.
  42. Bradding P. Human mast cell cytokines. Clin Exp Allergy. 1996;26:13-19.
  43. Ihara M, Urata H, Kinoshita A, Suzumiya J, Sasaguri M, Kikuchi M, Ideishi M, Arakawa K. Increased chymase-dependent angiotensin II formation in human atherosclerotic aorta. Hypertension. 1999;33:1399-1405.
  44. Tsunemi K, Takai S, Nishimoto M, Yuda A, Hasegawa S, Sawada Y, Fukumoto H, Sasaki S, Miyazaki M. Possible roles of angiotensin II-forming enzymes, angiotensin converting enzyme and chymase-like enzyme, in the human aneurysmal aorta. Hypertens Res. 2002;25:817-822.
  45. Doggrell SA, Wanstall JC. Vascular chymase: pathophysiological role and therapeutic potential of inhibition. Cardiovasc Res. 2004;61:653-662.
  46. Henningsson F, Wolters P, Chapman HA, Caughey GH, Pejler G. Mast cell cathepsins C and S control levels of carboxypeptidase A and the chymase, mouse mast cell protease 5. Biol Chem. 2003;384:1527-15

Guo-Ping Shi, DSc. Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115.