Kv7.4钾离子通道在血管炎症中的作用及分子机制

Vascular inflammation is an important aetiological factor for cardiovascular diseases, which is associated with all stages of abdominal aortic aneurysm and restenosis progression. Ion channel functions are closely related to vascular homeostasis. Our previous work showed that the incidence of abdominal aortic aneurysm and the degree of vascular intimal hyperplasia were significantly reduced in Kv7.4 potassium channel knockout mice. Transcriptomics and IPA upstream analysis indicated that NF-κB was inhibited in vascular tissue of Kv7.4 knockout mice. We hypothesis that Kv7.4 channel is able to crosstalk to inflammatory signaling pathways, enhance the sensitivity and the responding intensity of vascular cells for inflammatory stimuli, and promote the initiation and progression of vascular inflammatory diseases. In this project, we will screen and validate the differentially expressed genes in blood vessels from clinical and animal models; explore the specificity of vascular cells (smooth muscle, endothelial and monocyte-macrophage) in Kv7.4-mediated inflammatory response and activation of the key mechanism in TNFR1-IKKβ-IκBα-NF-κB signaling pathway; explore the feasibility of Kv7.4 channel specific inhibitors to alleviate vascular inflammatory disease. This study will help to clarify the significance of potassium channels in vascular inflammation and provide new possible targets and concept for clinical treatment of cardiovascular diseases.

血管炎症贯穿血管重构整个病理过程，离子通道功能与血管稳态调节密切相关。我们前期发现Kv7.4钾离子通道敲除小鼠的腹主动脉瘤发生率和损伤诱导的内膜增生程度显著低于野生型小鼠；转录组学和IPA分析提示Kv7.4通道敲除后血管组织差异基因的上游调节子NF-κB被抑制。据此提出假说，Kv7.4通道通过与炎症信号通路交谈，提高血管细胞对炎性刺激的敏感性和炎症应答强度，促进血管炎症性疾病的发生发展。本项目拟从临床及动物模型筛选和验证血管差显表达基因；探究Kv7.4通道介导炎症应答的血管细胞（平滑肌、内皮和单核巨噬细胞）特异性，血管细胞Kv7.4通道与TNFR1-IKKβ-IκBα-NF-κB信号通路级联活化的交谈机制和关键节点分子；探索Kv7.4通道特异性抑制剂干预血管炎症性疾病的新策略。此研究对深入认识钾离子通道在血管炎症中作用、发现新的致病机制和新的干预靶点具有重要意义和潜在的临床应用价值。

炎症现已成为促进心血管疾病发展的重要因素，也在血管内膜增生和腹主动脉瘤（AAA）形成中具关键作用。钾通道Kv7.4/KCNQ4，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未得到探索。本研究发现Kv7.4通道基因在在小鼠和人类的血管内膜和AAA组织中表达升高。基因敲除或药理学抑制小鼠Kv7.4通道，能通过下调系列炎症相关基因如基质金属蛋白酶（MMP）2/9和细胞间粘附分子1（ICAM-1）来缓解内膜增生和AAA形成，还能通过阻断血管平滑肌细胞（VSMCs）中肿瘤坏死因子受体1（TNFR1）与TNFR1相关死亡结构域蛋白（TRADD）之间的相互作用，抑制TNFR1-核因子（NF）-κB信号通路的活化。Kv7.4敲低的体内试验证实了VSMCs表达的Kv7.4在血管炎症的重要角色。综上所述，本课题结果表明，Kv7.4能加重血管炎症反应，促进血管内膜增生和AAA形成，抑制Kv7.4通道有望作为血管炎性疾病的新型治疗策略。