Cardiac mast cells cause atrial fibrillation through PDGF-A–mediated fibrosis in pressure-overloaded mouse hearts
Chien-hui Liao, … , Haruaki Nakaya, Issei Komuro
Chien-hui Liao, … , Haruaki Nakaya, Issei Komuro
Published December 21, 2009
Citation Information: J Clin Invest. 2010;120(1):242-253. https://doi.org/10.1172/JCI39942.
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Cardiac mast cells cause atrial fibrillation through PDGF-A–mediated fibrosis in pressure-overloaded mouse hearts

Abstract

Atrial fibrillation (AF) is a common arrhythmia that increases the risk of stroke and heart failure. Here, we have shown that mast cells, key mediators of allergic and immune responses, are critically involved in AF pathogenesis in stressed mouse hearts. Pressure overload induced mast cell infiltration and fibrosis in the atrium and enhanced AF susceptibility following atrial burst stimulation. Both atrial fibrosis and AF inducibility were attenuated by stabilization of mast cells with cromolyn and by BM reconstitution from mast cell–deficient WBB6F1-KitW/W-v mice. When cocultured with cardiac myocytes or fibroblasts, BM-derived mouse mast cells increased platelet-derived growth factor A (PDGF-A) synthesis and promoted cell proliferation and collagen expression in cardiac fibroblasts. These changes were abolished by treatment with a neutralizing antibody specific for PDGF α-receptor (PDGFR-α). Consistent with these data, upregulation of atrial Pdgfa expression in pressure-overloaded hearts was suppressed by BM reconstitution from WBB6F1-KitW/W-v mice. Furthermore, injection of the neutralizing PDGFR-α–specific antibody attenuated atrial fibrosis and AF inducibility in pressure-overloaded hearts, whereas administration of homodimer of PDGF-A (PDGF-AA) promoted atrial fibrosis and enhanced AF susceptibility in normal hearts. Our results suggest a crucial role for mast cells in AF and highlight a potential application of controlling the mast cell/PDGF-A axis to achieve upstream prevention of AF in stressed hearts.

Authors

Chien-hui Liao, Hiroshi Akazawa, Masaji Tamagawa, Kaoru Ito, Noritaka Yasuda, Yoko Kudo, Rie Yamamoto, Yukako Ozasa, Masanori Fujimoto, Ping Wang, Hiromitsu Nakauchi, Haruaki Nakaya, Issei Komuro

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Figure 3

Attenuation of AF and atrial fibrosis by mast cell stabilization by cromolyn.

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Attenuation of AF and atrial fibrosis by mast cell stabilization by crom...
(A) Scatter plot of the duration of AF episodes occurring during 3 series of bursts in Langendorff-perfused hearts (n = 10). (B) Incidence of AF episodes during 3 series of bursts under Langendorff perfusion (n = 10). *P < 0.05 versus sham; #P < 0.05 versus TAC treated with vehicle. (C) Mean duration of AF episodes during 3 series of bursts under Langendorff perfusion (n = 10). **P < 0.01 versus sham; ##P < 0.01 versus TAC treated with vehicle. (D) Representative surface ECG in lead-II deflection of AF induced by termination of the burst of transesophageal atrial pacing in TAC-operated mice. (E) High-magnification view of the section delineated by shaded box in D, showing AF with chaotic atrial rhythm and irregular ventricular response. (F) High-magnification view of the section delineated by shaded box in D. AF was spontaneously converted to sinus rhythm. (G) Incidence of AF episodes during 3 series of transesophageal bursts (n = 6). (H) Mean duration of AF episodes during 3 series of transesophageal bursts (n = 6). (I) Representative histological sections with Masson’s trichrome staining for visualization of atrial fibrosis (blue staining). Scale bars: 20 μm. (J) Hydroxyproline content in the atrium. Number of mice for each experiment is indicated in the bars. **P < 0.01 versus sham; ##P < 0.01 versus TAC treated with vehicle. Data are presented as mean ± SEM.