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Remodeled connexin 43 hemichannels alter cardiac excitability and promote arrhythmias
Mauricio A Lillo1, Manuel Muñoz2, Paula Rhana2
1Department of Pharmacology, Physiology and Neuroscience, Rutgers University, New Jersey Medical School, Newark, NJ, USA.
Insights
Opening remodeled Connexin-43 (Cx43) hemichannels is sufficient to cause cardiac arrhythmias during stress. Blocking these hemichannels prevents stress-induced arrhythmias and cellular dysfunction, suggesting a general mechanism for arrhythmogenesis.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Electrophysiology
Background:
- Connexin-43 (Cx43) is crucial for cardiac function, forming gap junction channels (GJCs) in ventricular cardiomyocytes.
- Cx43 remodeling is observed in cardiac pathologies and linked to ventricular arrhythmias, but mechanisms remain unclear.
- Previous studies implicated remodeled Cx43 hemichannels in arrhythmias within a specific cardiomyopathy model.
Purpose of the Study:
- To determine if opening remodeled Cx43 hemichannels generally alters cardiac excitability, independent of specific cardiomyopathy-associated cellular dysfunction.
- To investigate the role of Cx43 hemichannel opening in stress-induced cardiac arrhythmias.
Main Methods:
- Utilized a genetically modified Cx43 knock-in mouse (S3A) exhibiting Cx43 remodeling without intrinsic cardiac dysfunction.
- Administered isoproterenol (Iso) to induce cardiac stress in S3A and wild-type (WT) mice.
- Assessed arrhythmias using electrocardiography and evaluated cardiomyocyte function (membrane permeability, depolarization, Ca2+ overload) in vitro.
- Tested the efficacy of Cx43 hemichannel blockers (Gap19) in preventing Iso-induced arrhythmias and cellular dysfunction.
Main Results:
- S3A mice, unlike WT mice, developed severe arrhythmias upon Iso administration.
- Cx43 hemichannel blockade with Gap19 prevented Iso-induced arrhythmias in S3A mice.
- Iso-treated S3A cardiomyocytes exhibited increased membrane permeability, depolarization, and Ca2+ overload, leading to prolonged action potentials and triggered activity.
- These cellular dysfunctions were ameliorated by Cx43 hemichannel blockers.
Conclusions:
- Opening of remodeled Cx43 hemichannels is sufficient to induce cardiac arrhythmias during beta-adrenergic stress.
- This mechanism of Cx43 hemichannel opening contributes to cardiac excitability alterations and arrhythmogenicity, irrespective of the underlying cardiomyopathy.
- Targeting Cx43 hemichannels represents a potential therapeutic strategy for preventing stress-induced arrhythmias.
Abstract:
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.
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