Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury.
Nrf2/Keap1 system regulates vascular smooth muscle cell apoptosis for vascular homeostasis: role in neointimal formation after vascular injury.
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DOI：
10.1038/srep26291
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发表时间：
2016-05-20
影响因子：
4.6
通讯作者：
Numazawa S
中科院分区：
文献类型：
--
作者：
Ashino T;Yamamoto M;Numazawa S
血管损伤后内膜区域血管平滑肌细胞（VSMCs）的异常增加是发展新生内膜增生的关键事件。在血管重建过程中，血管平滑肌细胞的增殖和凋亡受到严格控制，以维持血管功能。NF-E2相关因子2（Nrf 2）/Kelch-like ECH相关蛋白1（Keap 1）系统是维持体内平衡的氧化应激反应的关键组成部分，在血管损伤后新生内膜增生中发挥重要作用，但Nrf 2/Keap 1在VSMC凋亡中的作用尚未阐明。在这里，我们报告，小鼠动脉损伤后14天，TUNEL阳性VSMCs检测到的新生内膜和中层。这些层含有表达高水平Nrf 2但低Keap 1表达的细胞。在VSMC中，Keap 1缺失诱导凋亡的特征，如阳性TUNEL染色和膜联蛋白V结合。这些变化与核Nrf 2的表达增加有关。同时Nrf 2耗竭抑制Keap 1耗竭诱导的细胞凋亡。在血管损伤后14天，Nrf 2缺陷小鼠表现出更少的TUNEL阳性细胞和增加的新生内膜和中膜区域的新生内膜形成。结果表明，Nrf 2/Keap 1系统在新生内膜形成过程中调节VSMC凋亡，从而抑制血管损伤后的新生内膜增生。
Abnormal increases in vascular smooth muscle cells (VSMCs) in the intimal region after a vascular injury is a key event in developing neointimal hyperplasia. To maintain vascular function, proliferation and apoptosis of VSMCs is tightly controlled during vascular remodeling. NF-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1) system, a key component of the oxidative stress response that acts in maintaining homeostasis, plays an important role in neointimal hyperplasia after a vascular injury; however, the role of Nrf2/Keap1 in VSMC apoptosis has not been clarified. Here we report that 14 days after arterial injury in mice, TUNEL-positive VSMCs are detected in both the neointimal and medial layers. These layers contain cells expressing high levels of Nrf2 but low Keap1 expression. In VSMCs, Keap1 depletion induces features of apoptosis, such as positive TUNEL staining and annexin V binding. These changes are associated with an increased expression of nuclear Nrf2. Simultaneous Nrf2 depletion inhibits Keap1 depletion-induced apoptosis. At 14 days after the vascular injury, Nrf2-deficient mice demonstrated fewer TUNEL-positive cells and increased neointimal formation in the neointimal and medial areas. The results suggest that the Nrf2/Keap1 system regulates VSMC apoptosis during neointimal formation, thereby inhibiting neointimal hyperplasia after a vascular injury.