Menick Donald R, Renaud Ludivine, Buchholz Avery, Müller Joachim G, Zhou Hongming, Kappler Christiana S, Kubalak Steven W, Conway Simon J, Xu Lin
Division of Cardiology, Department of Medicine, Gazes Cardiac Research Institute, Medical University of South Carolina, 114 Doughty St., Charleston, SC 29425, USA.
Ann N Y Acad Sci. 2007 Mar;1099:195-203. doi: 10.1196/annals.1387.058.
The Na+/Ca2+ exchanger (NCX1) is crucial in the regulation of [Ca2+]i in the cardiac myocyte. The exchanger is upregulated in cardiac hypertrophy, ischemia, and failure. This upregulation can have an effect on Ca2+ transients and possibly contribute to diastolic dysfunction and an increased risk of arrhythmias. Studies from both in vivo and in vitro model systems have provided an initial skeleton of the potential signaling pathways that regulate the exchanger during development, growth, and hypertrophy. The Ncx1 gene is upregulated in response to alpha-adrenergic stimulation. We have shown that this is via p38alpha activation of transcription factors binding to the Ncx1 promotor at the -80 CArG element. Interestingly, most of the elements, including the CArG element, which we have demonstrated to be important for regulation of Ncx1 expression are in the proximal 184 bp of the promotor. Using a transgenic mouse, we have shown that the proximal 184 bp is sufficient for expression of reporter genes in adult cardiomyocytes and for the correct spatiotemporal pattern of Ncx1 expression in development but not for upregulation in response to pressure overload.
钠钙交换体（NCX1）在调节心肌细胞内的[Ca2+]i方面至关重要。该交换体在心肌肥大、缺血和衰竭时上调。这种上调会影响Ca2+瞬变，并可能导致舒张功能障碍和心律失常风险增加。体内和体外模型系统的研究提供了在发育、生长和肥大过程中调节该交换体的潜在信号通路的初步框架。Ncx1基因在α-肾上腺素能刺激下上调。我们已经表明，这是通过p38α激活与Ncx1启动子-80 CArG元件结合的转录因子实现的。有趣的是，我们已证明对Ncx1表达调节很重要的大多数元件，包括CArG元件，都在启动子的近端184 bp内。使用转基因小鼠，我们已经表明近端184 bp足以在成年心肌细胞中表达报告基因，并足以在发育过程中实现Ncx1表达的正确时空模式，但不足以在压力过载时上调。
