Kcnh2 mediates FAK/AKT-FOXO3A pathway to attenuate sepsis-induced cardiac dysfunction.
Kcnh2 mediates FAK/AKT-FOXO3A pathway to attenuate sepsis-induced cardiac dysfunction.
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Kcnh2 介导 FAK/AKT-FOXO3A 通路减轻脓毒症引起的心功能障碍
DOI：
10.1111/cpr.12962
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发表时间：
2021-03
影响因子：
8.5
通讯作者：
Peng L
中科院分区：
文献类型：
--
作者：
Li Z;Meng Y;Liu C;Liu H;Cao W;Tong C;Lu M;Li L;Peng L
心肌功能障碍是脓毒症的一个重要表现，其死亡率较高。尽管已有迹象表明Kcnh2与病理过程有关，但其涉及的信号通路仍不明确。
采用盲肠结扎穿孔（CLP）手术或脂多糖（LPS）注射诱导脓毒性心功能障碍。采用蛋白质印迹法测定KCNH2的表达。在Kcnh2基因敲除（Kcnh2 +/ - ）大鼠和NS1643注射大鼠中，于CLP和LPS注射6小时后通过超声心动图检测心功能（每组n≥6）。在CLP诱导的脓毒症后监测生存率（每组n≥8）。
脓毒症可下调大鼠心脏以及LPS刺激的心肌细胞（而非心脏成纤维细胞）中的KCNH2水平。Kcnh2缺陷（Kcnh2 +/ - ）在LPS刺激下显著加重脓毒性心功能障碍，加剧组织损伤并增加细胞凋亡。Kcnh2 +/ - 组的缩短分数和射血分数值较Kcnh2 +/ + 组显著降低。与Kcnh2 +/ + 大鼠相比，Kcnh2 +/ - 脓毒症大鼠的生存结果明显恶化。然而，用NS1643激活Kcnh2则产生相反的效果。Kcnh2缺乏导致FAK/AKT信号通路受到抑制，表现为FOXO3A及其下游靶点上调，最终诱导心肌细胞凋亡和心脏组织损伤。无论是用激活剂激活AKT，还是用si - RNA敲低FOXO3A，都能显著减轻Kcnh2缺陷所介导的病理表现。
Kcnh2通过调节FAK/AKT - FOXO3A阻断LPS诱导的心肌细胞凋亡，在脓毒症诱导的心功能障碍（SCID）中起保护作用，表明钾通道在SCID的病理生理学中具有潜在作用。
示意图展示了脓毒症刺激后Kcnh2调节心功能障碍的机制。脓毒症诱导的Kcnh2减少导致心肌细胞中AKT受到抑制。由Kcnh2介导的心肌细胞AKT减弱上调了FOXO3A的表达，从而启动了BIM/PUMA基因的转录。最后，增强的BIM/PUMA导致心肌细胞凋亡，进而导致心功能障碍。
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. 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). 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. 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. Schematic representation shows the mechanisms of Kcnh2‐modulated cardiac dysfunction following sepsis stimulus. Sepsis‐induced decrease of Kcnh2 resulted in inhibition of AKT in cardiomyocytes. Attenuation of AKT of cardiomyocytes mediated by Kcnh2 upregulated FOXO3A expression, which initiated the transcription of BIM/PUMA genes. Finally, enhanced BIM/PUMA caused the cardiomyocytes apoptosis, leading to cardiac dysfunction.
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影响因子：
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