Ca2+-Calcineurin-NFAT4信号抑制巨噬细胞泡沫化和动脉粥样硬化形成及机制研究

我们前期研究(ATVB,2016)发现Orai1通道介导的Ca2+内流通过激活Calcineurin-ASK1而非经典的NFAT通路促进动脉粥样硬化发生，但Calcineurin-NFAT通路激活在动脉粥样硬化中的作用尚不清楚。预实验结果显示，巨噬细胞中主要表达NFAT4亚型。上调NFAT4可抑制清道夫受体表达和巨噬细胞泡沫化。由此，我们提出Calcineurin-NFAT4信号是抑制动脉粥样硬化形成的关键因素，即：激活NFAT4信号通过下调清道夫受体表达，减轻巨噬细胞泡沫化，进而抑制动脉粥样硬化形成。本研究拟在上述工作基础上，首先明确NFAT4激活对动脉粥样硬化形成的影响，并进而阐明NFAT4调控清道夫受体表达及巨噬细胞泡沫化的关键分子机制。本项目将揭示环孢霉素A等免疫抑制剂促进动脉粥样硬化形成的分子机理，同时为从NFAT4的角度寻找防治动脉粥样硬化新靶点提供科学依据。

Our previous study found that Orai1-mediated Ca2+ influx promoted atherosclerosis via activation of Calcineurin-ASK1 signaling pathway but not Calcineurin-NFAT pathway (ATVB, 2016). However, the functional role of Calcineurin-NFAT pathway in atherosclerosis remains unknown. Our primary data showed that NFAT4 is the dominat isoform expressed in macrophages. Upregulation of NFAT4 inhibited scavenger receptor expressions and foam cell formation, indicating Calcineurin-NFAT pathway plays a critical role in the development of atherosclerosis. Thus, we suppose that activation of Calcineurin-NFAT4 signaling pathway reduces scavenger receptor expressions and subsequently prevents foam cell formation, leading to inhibit atherosclerosis. The present study aims to investigate the effects of NFAT4 activation on atherosclerosis and how NFAT4 regulates scavenger receptor expressions and foam cell formation. This work will unveil the underlying mechanisms by which immunosuppressive drugs such as cyclosporine A promote atherosclerosis, and provide convinced evidences that NFAT4 may be a novel therapeutic target for the treatment of atherosclerosis.