Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts
Cardiac mast cells cause atrial fibrillation through PDGF-A-mediated fibrosis in pressure-overloaded mouse hearts
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DOI：
10.1172/jci39942
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发表时间：
2010-01-01
影响因子：
15.9
通讯作者：
Komuro, Issei
中科院分区：
文献类型：
--
作者：
Liao, Chien-hui;Akazawa, Hiroshi;Komuro, Issei
心房颤动（AF）是一种常见的心律失常，可增加中风和心力衰竭的风险。在这里，我们已经表明，肥大细胞，过敏和免疫反应的关键介质，在应激小鼠心脏的AF发病机制中起着至关重要的作用。压力超负荷诱导心房肥大细胞浸润和纤维化，增强心房短阵刺激后房颤易感性。心房纤维化和AF诱导均通过用克罗维因稳定肥大细胞和通过来自肥大细胞缺陷WBB 6 F1-Kit（W/W-v）小鼠的BM重建而减弱。当与心肌细胞或成纤维细胞共培养时，BM衍生的小鼠肥大细胞增加血小板衍生生长因子A（PDGF-A）的合成，并促进心脏成纤维细胞中的细胞增殖和胶原蛋白表达。这些变化通过用PDGF α-受体（PDGFR-α）特异性中和抗体治疗而消除。与这些数据一致，压力超负荷心脏中心房Pdgfa表达的上调被来自WBB 6 F1-Kit（W/W-v）小鼠的BM重建抑制。此外，注射PDGFR-α特异性中和抗体可减弱压力负荷过重心脏的心房纤维化和AF诱导，而给予PDGF-A（PDGF-AA）可促进正常心脏的心房纤维化并增强AF易感性。我们的研究结果表明肥大细胞在AF中的关键作用，并强调了控制肥大细胞/PDGF-A轴以实现应激心脏中AF的上游预防的潜在应用。
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-Kit(W/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-Kit(W/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 homodinier 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.