<em>Kcnh2</em> deletion is associated with rat embryonic development defects via destruction of KCNH2‑integrin β1 complex

Hu,Sangyu; Hu,Sangyu; Li,Zhigang; Li,Zhigang; Liu,Huan; Liu,Huan; Cao,Wenze; Cao,Wenze; Meng,Yilei; Meng,Yilei; Liu,Chang; Liu,Chang; He,Siyu; He,Siyu; Lin,Qin; Lin,Qin; Shang,Mengyue; Shang,Mengyue; Lin,Fang; Lin,Fang; Yi,Na; Yi,Na; Wang,Hanrui; Wang,Hanrui; Sachinidis,Agapios; Sachinidis,Agapios; Ying,Qilong; Ying,Qilong; Li,Li; Li,Li; Peng,Luying; Peng,Luying

doi:10.3892/ijmm.2023.5338

Kcnh2 deletion is associated with rat embryonic development defects via destruction of KCNH2‑integrin β1 complex

Authors:
- Sangyu Hu
- Zhigang Li
- Huan Liu
- Wenze Cao
- Yilei Meng
- Chang Liu
- Siyu He
- Qin Lin
- Mengyue Shang
- Fang Lin
- Na Yi
- Hanrui Wang
- Agapios Sachinidis
- Qilong Ying
- Li Li
- Luying Peng
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Affiliations: State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China, University of Cologne, Faculty of Medicine and University Hospital Cologne, Center for Physiology, Working Group Sachinidis, Center for Molecular Medicine, D-50931 Cologne, Germany, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
Published online on: December 7, 2023 https://doi.org/10.3892/ijmm.2023.5338
Article Number: 14
Copyright: © Hu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The Kv11.1 potassium channel encoded by the Kcnh2 gene is crucial in conducting the rapid delayed rectifier K⁺ current in cardiomyocytes. Homozygous mutation in Kcnh2 is embryonically lethal in humans and mice. However, the molecular signaling pathway of intrauterine fetal loss is unclear. The present study generated a Kcnh2 knockout rat based on edited rat embryonic stem cells (rESCs). Kcnh2 knockout was embryonic lethal on day 11.5 of development due to a heart configuration defect. Experiments with human embryonic heart single cells (6.5‑7 weeks post‑conception) suggested that potassium voltage‑gated channel subfamily H member 2 (KCNH2) plays a crucial role in the development of compact cardiomyocytes. By contrast, apoptosis was found to be triggered in the homozygous embryos, which could be attributed to the failure of KCNH2 to form a complex with integrin β1 that was essential for preventing the process of apoptosis via inhibition of forkhead box O3A. Destruction of the KCNH2/integrin β1 complex reduced the phosphorylation level of AKT and deactivated the glycogen synthase kinase 3 β (GSK‑3β)/β‑catenin pathway, which caused early developmental abnormalities in rats. The present work reveals a basic mechanism by which KCNH2 maintains intact embryonic heart development.

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