Journal Article

Kcnh2 mediates FAK/AKT‐FOXO3A pathway to attenuate sepsis‐induced cardiac dysfunction

Li, Zhigang, Li, Li, Meng, Yilei, Liu, Huan, Cao, Wenze, Lu, Min, Tong, Chang, Peng, Luying, Liu, Chang

2021

Overview

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. 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.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: AKT / AKT protein / Animals / Apoptosis / Apoptosis - drug effects / Cardiomyocytes / Cresols - pharmacology / Cytokines / Damage / Defects / Down-Regulation - drug effects / Echocardiography / ERG1 Potassium Channel - genetics / ERG1 Potassium Channel - metabolism / Experiments / Focal adhesion kinase / Focal Adhesion Kinase 1 - metabolism / Forkhead Box Protein O3 - antagonists & inhibitors / Forkhead Box Protein O3 - genetics / Forkhead Box Protein O3 - metabolism / FOXO3 protein / FOXO3A / Heart / Heart Diseases - etiology / Heart Diseases - mortality / Heart Diseases - veterinary / Injection / Kcnh2 / Kinases / Laboratory animals / Lipopolysaccharides / Lipopolysaccharides - pharmacology / Male / Monoclonal antibodies / Myocardium / Myocytes, Cardiac - cytology / Myocytes, Cardiac - drug effects / Myocytes, Cardiac - metabolism / Original / Phenylurea Compounds - pharmacology / Potassium channels / Proteins / Proto-Oncogene Proteins c-akt - agonists / Proto-Oncogene Proteins c-akt - metabolism / Rats / Rats, Sprague-Dawley / Rats, Transgenic / Ribonucleic acid / RNA / RNA Interference / RNA, Small Interfering - metabolism / Rodents / Sepsis / Sepsis - mortality / Sepsis - pathology / Sepsis - veterinary / sepsis‐induced cardiac dysfunction / Signal transduction / Signal Transduction - drug effects / Signaling / Surgery / Survival / Survival Rate / Western blotting