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Inhibition of NFAT suppresses foam cell formation and the development of diet-induced atherosclerosis
The FASEB Journal ( IF 4.8 ) Pub Date : 2021-09-22 , DOI: 10.1096/fj.202100947r
Meng Du 1, 2, 3 , Liu Yang 1, 2 , Bing Liu 1, 2 , Liuye Yang 1, 2 , Xiaoxiang Mao 1, 2 , Minglu Liang 2 , Kai Huang 1, 2, 3
Affiliation  

Deciphering the molecular and cellular processes involved in foam cell formation is critical for us to understand the pathogenesis of atherosclerosis. Nuclear factor of activated T cells (NFAT) is a transcription factor originally identified as a key player in the differentiation of T cells and maturation of immune system. Nowadays it has been brought into attention that NFAT also regulates multiple pathophysiological processes and targeted intervention in NFAT may be effective in the treatment of some cardiovascular diseases. However, whether NFAT is involved in foam cell formation remains elusive. NFAT in human monocyte-derived macrophage was activated by ox-LDL and translocated from the cytoplasm to the nucleus. NFAT then directly bound to peroxisome proliferator-activated receptor γ (PPARγ) in the nucleus and negatively regulated its transcriptional activity. NFATc2 knockdown or NFAT inhibitor 11R-VIVIT increased cholesterol efflux (by activating PPARγ-LXRα-ABCA1 cascade) and reduced the uptake of modified lipoprotein (in a PPARγ-independent way) in macrophage, thus prevented foam cell formation. Besides, 11R-VIVIT also exerted a protective role in the development of atherosclerosis in western diet-fed ApoE−/− mice. These results suggest NFAT inhibition as a potential therapeutic strategy in atherosclerosis.

中文翻译:

抑制 NFAT 抑制泡沫细胞的形成和饮食诱导的动脉粥样硬化的发展

破译泡沫细胞形成所涉及的分子和细胞过程对于我们了解动脉粥样硬化的发病机制至关重要。活化 T 细胞核因子 (NFAT) 是一种转录因子,最初被认为是 T 细胞分化和免疫系统成熟的关键参与者。如今,NFAT 还调节多种病理生理过程已引起人们的注意,靶向干预 NFAT 可能对某些心血管疾病的治疗有效。然而,NFAT 是否参与泡沫细胞形成仍然难以捉摸。人单核细胞衍生的巨噬细胞中的 NFAT 被 ox-LDL 激活并从细胞质转移到细胞核。然后 NFAT 直接与细胞核中的过氧化物酶体增殖物激活受体 γ (PPARγ) 结合,并对其转录活性进行负调节。NFATc2 敲低或 NFAT 抑制剂 11R-VIVIT 增加胆固醇流出(通过激活 PPARγ-LXRα-ABCA1 级联反应)并减少巨噬细胞对修饰脂蛋白的摄取(以 PPARγ 非依赖性方式),从而防止泡沫细胞形成。此外,11R-VIVIT 还在西方饮食喂养的 ApoE 中对动脉粥样硬化的发展发挥了保护作用-/-小鼠。这些结果表明 NFAT 抑制是动脉粥样硬化的潜在治疗策略。
更新日期:2021-09-23
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