Key result
Cardiac-specific deficiency of Cx43 in mice increased susceptibility to triggered arrhythmias due to enhanced sarcoplasmic reticulum Ca2+ leak, an effect that was suppressed by the mitochondrial KATP channel opener diazoxide.
Why the study?
Connexin43 exists as hemichannels in the inner mitochondrial membrane, but how mitochondrial Cx43 and mitochondrial KATP channels affect triggered arrhythmias remained unclear.
Deficiency of mitochondrial Cx43 increases susceptibility to triggered arrhythmias via increased ROS and SR Ca2+ leak, which can be compensated by opening mitochondrial KATP channels.
Answers are grounded in this paper and cite their sources.
Mitochondrial Cx43 may influence triggered arrhythmias in mice; hypothesis-generating for human arrhythmia mechanisms.
Aim : Connexin43 (Cx43) exits as hemichannels in the inner mitochondrial membrane. We examined how mitochondrial Cx43 and mitochondrial KATP channels affect the occurrence of triggered arrhythmias. Methods and Results : To generate cardiac-specific Cx43-deficient ( cCx43-/- ) mice, Cx43flox/flox mice were crossed with α-MHC ( Myh6 ) -cre+/- mice. The resulting offspring, Cx43flox/flox/ Myh6-cre+/- mice ( cCx43-/- mice) and their littermates ( cCx43+/+ mice), were used. Trabeculae were dissected from right ventricles of mouse hearts. Cardiomyocytes were enzymatically isolated from ventricles of mouse hearts. Force was measured with a strain gauge in trabeculae (22°C). To assess arrhythmia susceptibility, the minimal extracellular Ca2+ concentration ([Ca2+]o,min), at which arrhythmias were induced by electrical stimulation, was determined in trabeculae. ROS production was estimated with 2’,7’-dichlorofluorescein (DCF), mitochondrial membrane potential with tetramethylrhodamine methylester(TMRM), and Ca2+ spark frequency with fluo-4 and confocal microscopy in cardiomyocytes. Mitochondrial Ca2+ was estimated with rhod-2 in trabeculae. Diazoxide was used to open mitochondrial KATP. Most of cCx43-/- mice died suddenly within 8 weeks. Cx43 was present in the inner mitochondrial membrane in cCx43+/+ mice, but not in cCx43-/- mice. In cCx43-/- mice, the [Ca2+]o,min was lower, Ca2+ spark frequency and DCF oxidation rate were more increased, and TMRM fluorescence was more decreased. These changes in cCx43-/- mice were suppressed by diazoxide. Besides, in cCx43-/- mice, antioxidant peptide SS-31 increased the [Ca2+]o,min. Rhod-2 fluorescence was increased at high [Ca2+]o only in Cx43-/- mice. Conclusions : These results suggest that the deficiency of Cx43 activates Ca2+ leak from the SR probably due to an increase in ROS production, depolarization of mitochondrial membrane potential, and an increase in mitochondrial Ca2+, thereby causing triggered arrhythmias and that the deficiency of Cx43 hemichannels may be compensated by activation of mitochondrial KATP channels in mouse hearts.
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Sato et al. (2022) studied Triggered arrhythmias. Cardiac-specific Cx43 deficiency vs. Wild-type littermates (cCx43+/+) was evaluated on Minimal extracellular Ca2+ concentration ([Ca2+]o,min) at which arrhythmias were induced (p=<0.01). Cardiac-specific deficiency of Cx43 in mice increased susceptibility to triggered arrhythmias due to enhanced sarcoplasmic reticulum Ca2+ leak, an effect that was suppressed by the mitochondrial KATP channel opener diazoxide.
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