Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.
Kv7.4 channel is a key regulator of vascular inflammation and remodeling in neointimal hyperplasia and abdominal aortic aneurysms.
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DOI：
10.1016/j.freeradbiomed.2021.11.041
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发表时间：
2021-12
影响因子：
7.4
通讯作者：
Xizhenzi Fan;Ying-Ying Wang-Ying;Zi Y Cui;Zi-Hao Cheng;Hai-lin Zhang;N. Gamper;Fan Zhang;Mei Han
中科院分区：
文献类型：
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作者：
Xizhenzi Fan;Ying-Ying Wang-Ying;Zi Y Cui;Zi-Hao Cheng;Hai-lin Zhang;N. Gamper;Fan Zhang;Mei Han
炎症最近已成为心血管疾病发展的重要因素，并在新生内膜增生和腹主动脉瘤（AAA）形成的发展中发挥关键作用。Kv7.4/KCNQ 4是一种K+通道，是血管功能的重要调节因子之一，但其在血管炎症中的作用尚不清楚。在这里，我们发现Kv7.4通道的表达在小鼠和人的新生内膜和AAA组织中升高。基因缺失或药物抑制小鼠Kv7.4通道可通过下调一组血管炎症相关基因、基质金属蛋白酶（MMP）2/9和细胞间粘附分子（ICAM-1）减轻新生内膜增生和AAA形成。此外，Kv7.4通道的基因缺失或抑制可通过阻断肿瘤坏死因子受体1（TNFR 1）与肿瘤坏死因子受体1相关死亡结构域蛋白（TRADD）的相互作用，抑制血管平滑肌细胞（VSMCs）中肿瘤坏死因子受体1（TNFR 1）-核因子（NF）-κB信号通路的激活。Kv7.4在体内的敲低证实了VSMC表达的Kv7.4是血管炎症的主要因素。总之，我们的研究结果表明，Kv7.4通道介导血管炎症反应，促进新生内膜增生和AAA形成。抑制Kv7.4通道可能是治疗血管炎性疾病的一种新策略。
Inflammation has recently emerged as an important contributor for cardiovascular disease development and participates pivotally in the development of neointimal hyperplasia and abdominal aortic aneurysms (AAA) formation. Kv7.4/KCNQ4, a K+channel, is one of the important regulators of vascular function but its role in vascular inflammation is unexplored. Here, we showed that the expression of Kv7.4 channel was elevated in the neointima and AAA tissues from mice and humans. Genetic deletion or pharmacological inhibition of Kv7.4 channel in mice alleviated neointimal hyperplasia and AAA formation via downregulation of a set of vascular inflammation-related genes, matrix metalloproteinases (MMP) 2/9, and intercellular adhesion molecule (ICAM-1). Furthermore, genetic deletion or inhibition of Kv7.4 channel suppressed the activation of tumor necrosis factor receptor 1 (TNFR1)-nuclear factor (NF)-κB signaling pathway via blockade of interaction between TNFR1 and TNFR1-associated death domain protein (TRADD) in vascular smooth muscle cells (VSMCs). Knockdown of Kv7.4in vivoidentified VSMC-expressed Kv7.4 as a major factor in vascular inflammation. Collectively, our findings suggest that Kv7.4 channel aggravates vascular inflammatory response, which promotes the neointimal hyperplasia and AAA formation. Inhibition of Kv7.4 channel may be a novel therapeutic strategy for vascular inflammatory diseases.