Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts.
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 alpha-receptor (PDGFR-alpha). 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-alpha-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.
Liao
Chien-hui
CH
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan.
Akazawa
Hiroshi
H
Tamagawa
Masaji
M
Ito
Kaoru
K
Yasuda
Noritaka
N
Kudo
Yoko
Y
Yamamoto
Rie
R
Ozasa
Yukako
Y
Fujimoto
Masanori
M
Wang
Ping
P
Nakauchi
Hiromitsu
H
Nakaya
Haruaki
H
Komuro
Issei
I
D000818:Animals; D001281:Atrial Fibrillation / Q000209:etiology*; D001794:Blood Pressure; D001854:Bone Marrow Cells / Q000502:physiology; D004205:Cromolyn Sodium / Q000494:pharmacology; D005355:Fibrosis; D008407:Mast Cells / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009206:Myocardium / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000502:physiology*; D010982:Platelet-Derived Growth Factor / Q000502:physiology*; D019009:Proto-Oncogene Proteins c-kit / Q000502:physiology; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000502:physiology
D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha; D004205:Cromolyn Sodium