NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment
NFAT5 promotes arteriogenesis via MCP-1-dependent monocyte recruitment
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NFAT5 通过 MCP-1 依赖性单核细胞募集促进动脉生成
DOI：
10.1111/jcmm.14904
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发表时间：
2019-12-28
影响因子：
5.3
通讯作者：
Zhang，Guo-Gang
中科院分区：
文献类型：
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作者：
Lin，Xing-Chi;Pan，Miao;Zhang，Guo-Gang
研究表明，活化T细胞核因子5（NFAT 5）不仅是一种张力反应性转录因子，而且还能被其他刺激物激活，因此我们旨在研究NFAT 5是否参与大鼠侧支动脉的形成。我们对大鼠进行股动脉结扎（FAL）建立后肢缺血模型，发现与假手术组相比，FAL大鼠内收肌中NFAT 5表达上调。通过局部注射腺病毒介导的NFAT 5-shRNA敲低大鼠的NFAT 5显著抑制后肢血液灌注恢复和动脉生成。此外，NFAT 5敲低降低了大鼠内收肌中的巨噬细胞浸润和单核细胞趋化蛋白-1（MCP-1）表达。在体外，通过白细胞介素-1 β（IL-1β）刺激和功能丧失研究，我们证明NFAT 5敲低抑制内皮细胞中MCP-1的表达和ERK 1/2通路调节的THP-1细胞的趋化性。更重要的是，外源性MCP-1递送可以恢复FAL后大鼠的后肢血液灌注，促进动脉生成和巨噬细胞浸润，这些都被NFAT 5敲低所抑制。此外，NFAT 5敲低也抑制大鼠腓肠肌中的血管生成。我们的研究结果表明，NFAT 5是通过MCP-1依赖性单核细胞募集的动脉生成和血管生成的关键调节因子，这表明NFAT 5可能代表缺血性疾病的替代治疗靶点。
Studies have demonstrated that nuclear factor of activated T cells 5 (NFAT5) is not only a tonicity‐responsive transcription factor but also activated by other stimuli, so we aim to investigate whether NFAT5 participates in collateral arteries formation in rats. We performed femoral artery ligature (FAL) in rats for hindlimb ischaemia model and found that NFAT5 was up‐regulated in rat adductors with FAL compared with sham group. Knockdown of NFAT5 with locally injection of adenovirus‐mediated NFAT5‐shRNA in rats significantly inhibited hindlimb blood perfusion recovery and arteriogenesis. Moreover, NFAT5 knockdown decreased macrophages infiltration and monocyte chemotactic protein‐1 (MCP‐1) expression in rats adductors. In vitro, with interleukin‐1β (IL‐1β) stimulation and loss‐of‐function studies, we demonstrated that NFAT5 knockdown inhibits MCP‐1 expression in endothelial cells and chemotaxis of THP‐1 cells regulated by ERK1/2 pathway. More importantly, exogenous MCP‐1 delivery could recover hindlimb blood perfusion, promote arteriogenesis and macrophages infiltration in rats after FAL, which were depressed by NFAT5 knockdown. Besides, NFAT5 knockdown also inhibited angiogenesis in gastrocnemius muscles in rats. Our results indicate that NFAT5 is a critical regulator of arteriogenesis and angiogenesis via MCP‐1‐dependent monocyte recruitment, suggesting that NFAT5 may represent an alternative therapeutic target for ischaemic diseases.