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Review
, 19 (1)

Mast Cells: Key Contributors to Cardiac Fibrosis

Affiliations
Review

Mast Cells: Key Contributors to Cardiac Fibrosis

Scott P Levick et al. Int J Mol Sci.

Abstract

Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis.

Keywords: TNF-α; chymase; collagen; extracellular matrix; heart; histamine; protease; tryptase.

Conflict of interest statement

The authors declare no conflict of interest. The funding sponsors had no role in the writing of this manuscript.

Figures

Figure 1
Figure 1
MC stabilization with nedocromil, or MC deficiency prevents cardiac fibrosis. (A) Quantification and representative picrosirius red-stained images (20× magnification) for left ventricle (LV) collagen volume fraction for Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and SHR treated with the MC stabilizer, nedocromil (Ned, 30 mg/kg/day), * = p < 0.05 vs WKY, † = p < 0.05 vs SHR; (B) representative images of picrosirius red stained LV collagen in control mice (LM/c-kit+/−), TNF-α overexpressing mice (MHCsTNF/c-kit+/−), and TNF-α overexpressing mice crossed with MC-deficient mice (MHCsTNF/c-kit−/−); (C) quantification of collagen volume fraction in control LM//c-kit+/− mice, MHCsTNF/c-kit+/− mice, and MHCsTNF/c-kit−/− mice; and (D) LV pressure-volume relationship for control LM//c-kit+/− mice, MHCsTNF/c-kit+/− mice, and MHCsTNF/c-kit−/− mice. * = p < 0.05 vs LM/c-kit+/−, † = p < 0.05 vs MHCsTNF/c-kit+/−. (Copied with permission from Levick et al., Hypertension, 2009;53:1041–1047 (A); and Zhang et al., Circulation, 2011;124:2106–2116 (BD)).
Figure 2
Figure 2
Schematic depicting potential MC activation stimuli and interactions with other cell types that lead to cardiac fibrosis. Candidates for cardiac MC activation include IgE, TNF-α, and C5a. These then cause the release of MC mediators including the proteases tryptase and chymase, TNF-α, histamine, and TGF-β1. These mediators can then have direct effects on cardiac fibroblasts, but may also contribute to an inflammatory response that then activates cardiac fibroblasts via numerous cytokines. IL-10 and estrogen likely oppose cardiac MC activation/degranulation.
Figure 3
Figure 3
Immunolabelling of chymase (A, green) and tryptase (B, red) in cardiac mast cells isolated from rats (400× magnification; Copied with permission from Morgan et al., Inflamm Res, 2008;57:1–6).
Figure 4
Figure 4
Picrosirius red-stained images of perivascular fibrosis in normal, paced (vehicle), and paced plus the chymase inhibitor SUNC8257 (Chy-I) dog hearts (100× magnification; Copied with permission from Matsumoto et al., Circulation, 2003;107:2555–2558).
Figure 5
Figure 5
Schematic depicting the possible interactions between MCs and fibroblasts in the heart. (Left) MCs may act in a paracrine manner to signal only to fibroblasts in their local area. This would limit direct MC-fibroblast interactions as a mechanism by which MCs cause fibrosis; (Right) Alternatively, MC products may be taken up in the general coronary circulation allowing their products to be distributed to fibroblasts throughout the heart. This would allow for greater MC-fibroblast interactions.

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