Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex

Chunlian Zhong; Huan Zhao; Xinwen Xie; Zhi Qi; Yumei Li; Lee Jia; Jinwei Zhang; Yusheng Lu

doi:10.3389/fphys.2022.815301

Protein Kinase C-Mediated Hyperphosphorylation and Lateralization of Connexin 43 Are Involved in Autoimmune Myocarditis-Induced Prolongation of QRS Complex

Front Physiol. 2022 Mar 28:13:815301. doi: 10.3389/fphys.2022.815301. eCollection 2022.

Authors

Chunlian Zhong^{1

2}, Huan Zhao³, Xinwen Xie⁴, Zhi Qi⁵, Yumei Li⁶, Lee Jia^{1

2}, Jinwei Zhang^{7

8}, Yusheng Lu^{1

2}

Affiliations

¹ School of Material and Chemical Engineering, Minjiang University, Fuzhou, China.
² Fuzhou Institute of Oceanography, Fuzhou, China.
³ State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Life Sciences, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, Xiamen University, Xiamen, China.
⁴ Liancheng County General Hospital, Longyan, China.
⁵ Department of Basic Medical Sciences, Medical College of Xiamen University, Xiamen, China.
⁶ School of Basic Medicine, Gannan Medical University, Ganzhou, China.
⁷ Xiamen Key Laboratory of Cardiovascular Disease, Xiamen Cardiovascular Hospital Xiamen University, Xiamen, China.
⁸ Hatherly Laboratories, Medical School, College of Medicine and Health, Institute of Biomedical and Clinical Sciences, University of Exeter, Exeter, United Kingdom.

Abstract

Myocarditis is a serious and potentially life-threatening disease, which leads to cardiac dysfunction and sudden cardiac death. An increasing number of evidence suggests that myocarditis is also a malignant complication of coronavirus pneumonia, associated with heart failure and sudden cardiac death. Prolonged QRS complexes that are related to malignant arrhythmias caused by myocarditis significantly increase the risk of sudden cardiac death in patients. However, the molecular mechanisms are not fully known at present. In this study, we identify protein kinase C (PKC) as a new regulator of the QRS complex. In isolated hearts of normal rats, the PKC agonist, phorbol-12-myristate-13-acetate (PMA), induced prolongation of the QRS complex. Mechanistically, hyperphosphorylation and lateralization of connexin 43 (Cx43) by PKC induced depolymerization and internalization of Cx43 gap junction channels and prolongation of the QRS duration. Conversely, administration of the PKC inhibitor, Ro-32-0432, in experimental autoimmune myocarditis (EAM) rats after the most severe inflammation period still significantly rescued the stability of the Cx43 gap junction and alleviated prolongation of the QRS complex. Ro-32-0432 reduced phosphorylation and blocked translocation of Cx43 in EAM rat heart but did not regulate the mRNA expression level of ventricular ion channels and the other regulatory proteins, which indicates that the inhibition of PKC might have no protective effect on ion channels that generate ventricular action potential in EAM rats. These results suggest that the pharmacological inhibition of PKC ameliorates the prolongation of the QRS complex via suppression of Cx43 hyperphosphorylation, lateralization, and depolymerization of Cx43 gap junction channels in EAM rats, which provides a potential therapeutic strategy for myocarditis-induced arrhythmias.

Keywords: QRS duration; connexin 43 channels; experimental autoimmune myocarditis; ion channels; protein kinase C.