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Kcnh2 mediates FAK/AKT‐FOXO3A pathway to attenuate sepsis‐induced cardiac dysfunction
Cell Proliferation ( IF 8.5 ) Pub Date : 2020-12-02 , DOI: 10.1111/cpr.12962
Zhigang Li 1, 2, 3, 4 , Yilei Meng 1, 2, 3, 4 , Chang Liu 1, 2, 3 , Huan Liu 1, 2, 3, 4 , Wenze Cao 1, 2, 3, 4 , Chang Tong 3 , Min Lu 3 , Li Li 1, 2, 3, 4, 5 , Luying Peng 1, 2, 3, 4, 5
Affiliation  

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.

中文翻译:

Kcnh2 介导 FAK/AKT-FOXO3A 通路以减轻败血症引起的心功能障碍

目的 心肌功能障碍是脓毒症的重要表现,导致高死亡率。即使 Kcnh2 已被暗示与病理过程有关,但其所涉及的信号仍然难以捉摸。材料与方法 进行盲肠结扎穿刺(CLP)手术或脂多糖(LPS)注射以诱发败血性心功能不全。蛋白质印迹用于确定 KCNH2 表达。在 Kcnh2 敲除 (Kcnh2+/-) 和 NS1643 注射大鼠(n ≥ 6/组)中注射 CLP 和 LPS 后 6 小时,通过超声心动图检查心脏功能。在 CLP 诱导的败血症(n ≥ 8/组)后监测存活率。结果脓毒症可以下调大鼠心脏以及 LPS 刺激的心肌细胞中的 KCNH2 水平,但不能下调心脏成纤维细胞。Kcnh2 (Kcnh2+/-) 的缺陷在 LPS 攻击下显着加重了败血性心脏功能障碍,加剧了组织损伤并增加了细胞凋亡。与Kcnh2+/+组相比,Kcnh2+/-组的缩短分数和射血分数显着降低。与 Kcnh2+/+ 大鼠相比,Kcnh2+/- 败血症大鼠的生存结果显着恶化。然而,用 NS1643 激活 Kcnh2 会产生相反的效果。Kcnh2 的缺乏导致 FAK/AKT 信号传导的抑制,反映在 FOXO3A 及其下游靶点的上调,最终导致心肌细胞凋亡和心脏组织损伤。通过激活剂激活 AKT 或用 si-RNA 敲低 FOXO3A 显着减弱了 Kcnh2 缺陷介导的病理表现。
更新日期:2020-12-02
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