Mast cells (MCs) are recognized as essential effector cells in the elicitation of allergic response by releasing cytoplasmic granule remnants. Previous studies suggest that MCs also participate in leukocyte recruitment, foam cell formation, smooth muscle cell proliferation, and T cell migration and activation, all essential for atherosclerosis, an inflammatory disease involving sophisticated cell-cell interaction, cytokine production, and immune responses. Detection of increased MC accumulation in human atherosclerotic lesions suggests their participation in atherogenesis. MCs appear in highest density in atheroma shoulder regions, where they are prone to erosion and rupture, but appear only scarcely in the fibrous caps and unaffected aortae. However, it remains uncertain whether accumulation of MCs in atheromata directly affects atherogenesis or is merely one of the many hallmarks. Our recent preliminary studies suggest that MCs participate directly in atherogenesis. In mice, the accumulation of lesion MCs correlated with the progression of atherogenesis. Absence of MCs impaired atherogenesis by >50% after 26 weeks of an atherogenic diet. Reduced atheromata in MC-null mice can be fully restored by reconstituting the mice with wild-type MCs but not interleukin-6-deficient MCs. Furthermore, MC activation with MC destabilizer enhanced atherogenesis by nearly 30%. Lack of mechanistic explanations for these observations led to a central hypothesis that MCs directly affect atherogenesis by releasing inflammatory mediators to promote leukocyte recruitment and migration, macrophage foam cell formation, smooth muscle cell proliferation and migration, lymphocyte activation, and matrix-degrading protease expression. We propose three specific aims to test this hypothesis by examining whether absence of MCs affects atherogenesis and whether we can control atherosclerosis by regulating MC activation;identifying which molecules MCs use to influence vascular wall remodeling;and testing how MCs affect other vascular cells in vitro;whether absence of MCs affects the biology of other hematopoietic cells;and which mediators are required for MC migration and recruitment in vivo. Together, these lines of experiments should provide both in vitro and in vivo evidence of whether the pathogenesis of atherosclerosis requires MC functions, and result in detailed mechanistic explanations of how MCs might participate in the pathogenesis of this common vascular disorder.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL081090-03
Application #
7666256
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Ershow, Abby
Project Start
2007-09-15
Project End
2011-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$418,375
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Zhou, Yi; Chen, Huimei; Liu, Li et al. (2017) CD74 Deficiency Mitigates Systemic Lupus Erythematosus-like Autoimmunity and Pathological Findings in Mice. J Immunol 198:2568-2577
Liu, Cong-Lin; Santos, Marcela M; Fernandes, Cleverson et al. (2017) Toll-like receptor 7 deficiency protects apolipoprotein E-deficient mice from diet-induced atherosclerosis. Sci Rep 7:847
Zhou, Yi; Chen, Huimei; Liu, Li et al. (2017) Cathepsin K Deficiency Ameliorates Systemic Lupus Erythematosus-like Manifestations in Faslpr Mice. J Immunol 198:1846-1854
Liu, Cong-Lin; Wemmelund, Holger; Wang, Yi et al. (2016) Asthma Associates With Human Abdominal Aortic Aneurysm and Rupture. Arterioscler Thromb Vasc Biol 36:570-8
Liu, Cong-Lin; Wang, Yi; Liao, Mengyang et al. (2016) Allergic Lung Inflammation Aggravates Angiotensin II-Induced Abdominal Aortic Aneurysms in Mice. Arterioscler Thromb Vasc Biol 36:69-77
Liu, Cong-Lin; Wang, Yi; Liao, Mengyang et al. (2016) Allergic lung inflammation promotes atherosclerosis in apolipoprotein E-deficient mice. Transl Res 171:1-16
Liu, Cong-Lin; Zhang, Jin-Ying; Shi, Guo-Ping (2016) Interaction between allergic asthma and atherosclerosis. Transl Res 174:5-22
Wang, Jing; Sukhova, Galina K; Liu, Jian et al. (2015) Cathepsin G deficiency reduces periaortic calcium chloride injury-induced abdominal aortic aneurysms in mice. J Vasc Surg 62:1615-24
Bot, Ilze; Shi, Guo-Ping; Kovanen, Petri T (2015) Mast cells as effectors in atherosclerosis. Arterioscler Thromb Vasc Biol 35:265-71
Wang, Jing; Sun, Chongxiu; Gerdes, Norbert et al. (2015) Interleukin 18 function in atherosclerosis is mediated by the interleukin 18 receptor and the Na-Cl co-transporter. Nat Med 21:820-6

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