TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation.
TRPM7-mediated Ca2+ signals confer fibrogenesis in human atrial fibrillation.
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DOI：
10.1161/circresaha.109.206771
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发表时间：
2010-03-19
影响因子：
20.1
通讯作者：
Yue L
中科院分区：
文献类型：
--
作者：
Du J;Xie J;Zhang Z;Tsujikawa H;Fusco D;Silverman D;Liang B;Yue L
心房颤动（AF）是最持久的心律失常，也是发病率和死亡率的主要原因之一。尽管已经提出Ca2+信号参与纤维化促进，但Ca2+信号机制的分子基础以及Ca2+信号如何促进纤维化仍不清楚。为了确定人心房成纤维细胞中Ca2+可渗透通道的分子机制，并研究Ca2+信号如何促进人房颤的纤维形成。我们证明了瞬时受体电位美拉抑素相关7 （TRPM7）是人心房成纤维细胞中主要Ca2+可渗透通道的分子基础。心房成纤维细胞内源性TRPM7电流类似于异源表达的TRPM7的生物物理和药理学特性。通过小发夹RNA （shRNA）敲除TRPM7在很大程度上消除心房成纤维细胞中的TRPM7电流和Ca2+内流。更重要的是，来自房颤患者的心房成纤维细胞显示出TRPM7电流和Ca2+内流的显著上调，并且更容易向肌成纤维细胞分化，可能是由于TRPM7的表达增强。TRPM7-shRNA显著降低基底心房颤动成纤维细胞分化。转化生长因子β1 （TGF-β1）是心房纤维化的主要刺激物，它需要trpm7介导的Ca2+信号才能影响成纤维细胞的增殖和分化。TGF-β1诱导培养的人心房成纤维细胞分化与TGF-β1诱导的TRPM7表达升高密切相关。我们的研究结果表明，TRPM7是人心房成纤维细胞中主要的Ca2+可渗透通道，可能在TGF-β1诱导的房颤纤维形成中起重要作用。
Cardiac fibrosis contributes to pathogenesis of atrial fibrillation (AF), which is the most sustained arrhythmia and a major cause of morbidity and mortality. Although it has been suggested that Ca2+ signals are involved in fibrosis promotion, the molecular basis of Ca2+ signaling mechanisms and how Ca2+ signals contribute to fibrogenesis remain unknown. To determine the molecular mechanisms of Ca2+-permeable channel(s) in human atrial fibroblasts, and to investigate how Ca2+ signals contribute to fibrogenesis in human AF. We demonstrate that the transient receptor potential melastatin related 7 (TRPM7) is the molecular basis of the major Ca2+-permeable channel in human atrial fibroblasts. Endogenous TRPM7 currents in atrial fibroblasts resemble the biophysical and pharmacological properties of heterologous expressed TRPM7. Knocking down TRPM7 by small hairpin RNA (shRNA) largely eliminates TRPM7 current and Ca2+ influx in atrial fibroblasts. More importantly, atrial fibroblasts from AF patients show a striking upregulation of both TRPM7 currents and Ca2+ influx and are more prone to myofibroblast differentiation, presumably due to the enhanced expression of TRPM7. TRPM7-shRNA markedly reduced basal AF fibroblast differentiation. Transforming growth factor β1 (TGF-β1), the major stimulator of atrial fibrosis, requires TRPM7-mediated Ca2+ signal for its effect on fibroblast proliferation and differentiation. Furthermore, TGF-β1 induced differentiation of cultured human atrial fibroblasts is well correlated with an increase of TRPM7 expression induced by TGF-β1. Our results establish that TRPM7 is the major Ca2+-permeable channel in human atrial fibroblasts, and likely plays an essential role in TGF-β1-elicited fibrogenesis in human AF.