Macrophage NFAT c3 prevents foam cell formation and atherosclerosis: evidence and mechanisms
Macrophage NFAT c3 prevents foam cell formation and atherosclerosis: evidence and mechanisms
复制标题
巨噬细胞 NFATc3 预防泡沫细胞形成和动脉粥样硬化：证据和机制。
DOI：
10.1093/eurheartj/ehab660
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发表时间：
2021-09-27
影响因子：
39.3
通讯作者：
Liang, Si-Jia
中科院分区：
文献类型：
--
作者：
Liu, Xiu;Guo, Jia-Wei;Liang, Si-Jia
旨在
我们以前的研究表明，通过巨噬细胞中的Orai 1储存操纵的Ca 2+通道的Ca 2+内流通过钙调神经磷酸酶-ASK 1途径而不是经典的钙调神经磷酸酶-活化T细胞核因子（NFAT）途径促进泡沫细胞形成和动脉粥样硬化。此外，巨噬细胞中NFATc 3的上调抑制泡沫细胞形成，表明巨噬细胞NFATc 3是动脉粥样硬化形成的负调节剂。因此，本研究调查了巨噬细胞NFATc 3在动脉粥样硬化形成中的确切作用。
方法和结果
产生巨噬细胞特异性NFATc 3敲除小鼠以确定NFATc 3对腺相关病毒突变体PCSK 9诱导的动脉粥样硬化的小鼠模型中的动脉粥样硬化的作用。在人类和小鼠动脉粥样硬化病变内的巨噬细胞中NFATc 3表达降低。此外，动脉粥样硬化患者外周血单核细胞中NFATc 3水平与斑块不稳定性呈负相关。此外，巨噬细胞特异性消融小鼠中的NFATc 3导致动脉粥样硬化斑块形成，而巨噬细胞特异性NFATc 3转基因小鼠表现出相反的表型。巨噬细胞中NFATc 3缺乏通过增强SR-A和CD 36介导的脂质摄取促进泡沫细胞形成。NFATc 3直接靶向并转录上调miR-204水平。成熟的miR-204- 5 p通过典型调节抑制SR-A表达。出乎意料的是，miR-204- 3 p定位于细胞核并抑制CD 36转录。miR-204的恢复消除了在巨噬细胞特异性NFATc 3敲除小鼠中观察到的致动脉粥样硬化表型，并且miR-204功能的阻断逆转了NFATc 3在巨噬细胞中的有益作用。
结论
巨噬细胞NFATc 3上调miR-204以降低SR-A和CD 36水平，从而防止泡沫细胞形成和动脉粥样硬化，表明NFATc 3/miR-204轴可能是抗动脉粥样硬化的潜在治疗靶点。
AIMS
Our previous study demonstrated that Ca2+ influx through the Orai1 store-operated Ca2+ channel in macrophages contributes to foam cell formation and atherosclerosis via the calcineurin-ASK1 pathway, not the classical calcineurin-nuclear factor of activated T-cell (NFAT) pathway. Moreover, up-regulation of NFATc3 in macrophages inhibits foam cell formation, suggesting that macrophage NFATc3 is a negative regulator of atherogenesis. Hence, this study investigated the precise role of macrophage NFATc3 in atherogenesis.
METHODS AND RESULTS
Macrophage-specific NFATc3 knockout mice were generated to determine the effect of NFATc3 on atherosclerosis in a mouse model of adeno-associated virus-mutant PCSK9-induced atherosclerosis. NFATc3 expression was decreased in macrophages within human and mouse atherosclerotic lesions. Moreover, NFATc3 levels in peripheral blood mononuclear cells from atherosclerotic patients were negatively associated with plaque instability. Furthermore, macrophage-specific ablation of NFATc3 in mice led to the atherosclerotic plaque formation, whereas macrophage-specific NFATc3 transgenic mice exhibited the opposite phenotype. NFATc3 deficiency in macrophages promoted foam cell formation by potentiating SR-A- and CD36-meditated lipid uptake. NFATc3 directly targeted and transcriptionally up-regulated miR-204 levels. Mature miR-204-5p suppressed SR-A expression via canonical regulation. Unexpectedly, miR-204-3p localized in the nucleus and inhibited CD36 transcription. Restoration of miR-204 abolished the proatherogenic phenotype observed in the macrophage-specific NFATc3 knockout mice, and blockade of miR-204 function reversed the beneficial effects of NFATc3 in macrophages.
CONCLUSION
Macrophage NFATc3 up-regulates miR-204 to reduce SR-A and CD36 levels, thereby preventing foam cell formation and atherosclerosis, indicating that the NFATc3/miR-204 axis may be a potential therapeutic target against atherosclerosis.