Kcnh2 通过介导 FAK/AKT-FOXO3A 通路来减轻脓毒症引起的心脏功能障碍。

OBJECTIVES: Myocardial dysfunction is a significant manifestation in sepsis, which results in high mortality. Even Kcnh2 has been hinted to associate with the pathological process, its involved signalling is still elusive. MATERIALS AND METHODS: The caecal ligation puncture (CLP) surgery or lipopolysaccharide (LPS) injection was performed to induce septic cardiac dysfunction. Western blotting was used to determine KCNH2 expression. Cardiac function was examined by echocardiography 6 hours after CLP and LPS injection in Kcnh2 knockout (Kcnh2 ) and NS1643 injection rats (n ≥ 6/group). Survival was monitored following CLP-induced sepsis (n ≥ 8/group). RESULTS: Sepsis could downregulate KCNH2 level in the rat heart, as well as in LPS-stimulated cardiomyocytes but not cardiac fibroblast. Defect of Kcnh2 (Kcnh2 ) significantly aggravated septic cardiac dysfunction, exacerbated tissue damage and increased apoptosis under LPS challenge. Fractional shortening and ejection fraction values were significantly decreased in Kcnh2 group than Kcnh2 group. Survival outcome in Kcnh2 septic rats was markedly deteriorated, compared with Kcnh2 rats. Activated Kcnh2 with NS1643, however, resulted in opposite effects. Lack of Kcnh2 caused inhibition of FAK/AKT signalling, reflecting in an upregulation for FOXO3A and its downstream targets, which eventually induced cardiomyocyte apoptosis and heart tissue damage. Either activation of AKT by activator or knockdown of FOXO3A with si-RNA remarkably attenuated the pathological manifestations that Kcnh2 defect mediated. CONCLUSION: Kcnh2 plays a protection role in sepsis-induced cardiac dysfunction (SCID) via regulating FAK/AKT-FOXO3A to block LPS-induced myocardium apoptosis, indicating a potential effect of the potassium channels in pathophysiology of SCID.

目的：心肌功能障碍是脓毒症的一个重要表现，可导致高死亡率。即使 Kcnh2 已被暗示与病理过程有关，但其涉及的信号通路仍不清楚。

材料和方法：采用盲肠结扎穿孔术（CLP）或脂多糖（LPS）注射诱导脓毒症性心功能障碍。采用 Western blot 检测 KCNH2 的表达。在 CLP 和 LPS 注射后 6 小时，通过超声心动图检查 Kcnh2 敲除（Kcnh2 ）和 NS1643 注射大鼠（每组 n≥6）的心脏功能。通过 CLP 诱导的脓毒症监测大鼠的存活率（每组 n≥8）。

结果：脓毒症可下调大鼠心脏以及 LPS 刺激的心肌细胞而非心肌成纤维细胞中的 KCNH2 水平。在 LPS 刺激下，Kcnh2 缺陷（Kcnh2 ）显著加重脓毒症性心功能障碍，加重组织损伤并增加细胞凋亡。与 Kcnh2 组相比，Kcnh2 组的短轴缩短率和射血分数值明显降低。与 Kcnh2 大鼠相比，Kcnh2 脓毒症大鼠的存活率明显恶化。然而，用 NS1643 激活 Kcnh2 则产生相反的效果。缺乏 Kcnh2 导致 FAK/AKT 信号通路被抑制，反映出 FOXO3A 及其下游靶标上调，最终导致心肌细胞凋亡和心脏组织损伤。用激活剂激活 AKT 或用 si-RNA 敲低 FOXO3A 均可显著减轻 Kcnh2 缺陷介导的病理表现。

结论：Kcnh2 通过调节 FAK/AKT-FOXO3A 来阻止 LPS 诱导的心肌细胞凋亡，在脓毒症诱导的心肌功能障碍（SCID）中发挥保护作用，提示钾通道在 SCID 的病理生理学中具有潜在作用。