Kcnh2 mediates FAK/AKT-FOXO3A pathway to attenuate sepsis-induced cardiac dysfunction
Zhigang Li
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorYilei Meng
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorChang Liu
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorHuan Liu
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorWenze Cao
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorChang Tong
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorMin Lu
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorCorresponding Author
Li Li
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, China
Correspondence
Luying Peng and Li Li, Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Emails: [email protected] (L. P.); [email protected] (L. L.)
Search for more papers by this authorCorresponding Author
Luying Peng
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, China
Correspondence
Luying Peng and Li Li, Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Emails: [email protected] (L. P.); [email protected] (L. L.)
Search for more papers by this authorZhigang Li
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorYilei Meng
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorChang Liu
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorHuan Liu
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorWenze Cao
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorChang Tong
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorMin Lu
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Search for more papers by this authorCorresponding Author
Li Li
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, China
Correspondence
Luying Peng and Li Li, Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Emails: [email protected] (L. P.); [email protected] (L. L.)
Search for more papers by this authorCorresponding Author
Luying Peng
Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Institute of Medical Genetics, Tongji University, Shanghai, China
Heart Health Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China
Department of Medical Genetics, Tongji University School of Medicine, Shanghai, China
Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Beijing, China
Correspondence
Luying Peng and Li Li, Key Laboratory of Arrhythmias, Ministry of Education, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Emails: [email protected] (L. P.); [email protected] (L. L.)
Search for more papers by this authorThis work was supported by grants from the National Natural Science Foundation of China (82070270, 81870242 grant to Dr Li Li; 32071109 grant to Dr Luying Peng; 81670208 grant to Dr Chang Tong; 81873429 grant to Dr Min Lu and M0048 grant to Dr Luying Peng), the Shanghai Committee of Science and Technology (18JC1414300 grant to Dr Li Li) and CAMS Innovation Fund for Medical Sciences (2019-I2M-5-053).
Abstract
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.
CONFLICT OF INTEREST
None declared.
Open Research
DATA AVAILABILITY STATEMENT
The data that support the findings of this study are available from the corresponding author upon reasonable request.
Supporting Information
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| cpr12962-sup-0012-SupInfo.docxWord document, 16.5 KB | Supplementary information |
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