Connexin-43 (Cx43) is the most abundant protein forming gap junction channels (GJCs) in cardiac ventricles. In multiple cardiac pathologies, including hypertrophy and heart failure, Cx43 is found remodeled at the lateral side of the intercalated discs of ventricular cardiomyocytes. Remodeling of Cx43 has been long linked to spontaneous ventricular arrhythmia, yet the mechanisms by which arrhythmias develop are still debated. Using a model of dystrophic cardiomyopathy, we previously showed that remodeled Cx43 function as aberrant hemichannels (non-forming GJCs) that alter cardiomyocyte excitability and, consequently, promote arrhythmias. Here, we aim to evaluate if opening of remodeled Cx43 can serve as a general mechanism to alter cardiac excitability independent of cellular dysfunction associated with a particular cardiomyopathy. To address this issue, we used a genetically modified Cx43 knock-in mouse (S3A) that promotes cardiac remodeling of Cx43 protein without apparent cardiac dysfunction. Importantly, when S3A mice were subjected to cardiac stress using the β-adrenergic agonist isoproterenol (Iso), they displayed acute and severe arrhythmias, which were not observed in WT mice. Pretreatment of S3A mice with the Cx43 hemichannel blocker, Gap19, prevented Iso-induced abnormal electrocardiographic behavior. At the cellular level, when compared with WT, Iso-treated S3A cardiomyocytes showed increased membrane permeability, greater plasma membrane depolarization, and Ca2+ overload, which likely caused prolonged action potentials, delayed after depolarizations, and triggered activity. All these cellular dysfunctions were also prevented by Cx43 hemichannel blockers. Our results support the notion that opening of remodeled Cx43 hemichannels, regardless of the type of cardiomyopathy, is sufficient to mediate cardiac-stress-induced arrhythmogenicity.
Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias
Disclosures: The authors declare no competing interests exist.
- Award Id(s): 18POST339610107,932684,23POST1027462,16GRNT31100022
- Award Id(s): R01HL92929,R01Hl133294,1R01HL141170-01,1R01GM099490
- Award Id(s): 416281
Mauricio A. Lillo, Manuel Muñoz, Paula Rhana, Kelli Gaul-Muller, Jonathan Quan, Natalia Shirokova, Lai-Hua Xie, Luis Fernando Santana, Diego Fraidenraich, Jorge E. Contreras; Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias. J Gen Physiol 3 July 2023; 155 (7): e202213150. doi: https://doi.org/10.1085/jgp.202213150
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