4.7 Article

Diazoxide Needs Mitochondrial Connexin43 to Exert Its Cytoprotective Effect in a Cellular Model of CoCl2-Induced Hypoxia

Journal

Publisher

MDPI
DOI: 10.3390/ijms222111599

Keywords

mCx43; K-ATP channels; diazoxide; chemical hypoxia

Funding

  1. University of Salerno [FARB 2020-ORSA209458, FARB 2020-ORSA208878]

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This study demonstrates a cooperative relationship between mCx43 and K-ATP channels in inducing cytoprotection in cardiomyocytes under hypoxic conditions. The presence of mCx43 is essential for the protective effects of diazoxide, an opener of K-ATP channels, against CoCl2-induced mitochondrial damage. These findings highlight the close functional link between mCx43 and K-ATP channels.
Hypoxia is the leading cause of death in cardiomyocytes. Cells respond to oxygen deprivation by activating cytoprotective programs, such as mitochondrial connexin43 (mCx43) overexpression and the opening of mitochondrial K-ATP channels, aimed to reduce mitochondrial dysfunction. In this study we used an in vitro model of CoCl2-induced hypoxia to demonstrate that mCx43 and K-ATP channels cooperate to induce cytoprotection. CoCl2 administration induces apoptosis in H9c2 cells by increasing mitochondrial ROS production, intracellular and mitochondrial calcium overload and by inducing mitochondrial membrane depolarization. Diazoxide, an opener of K-ATP channels, reduces all these deleterious effects of CoCl2 only in the presence of mCx43. In fact, our results demonstrate that in the presence of radicicol, an inhibitor of Cx43 translocation to mitochondria, the cytoprotective effects of diazoxide disappear. In conclusion, these data confirm that there exists a close functional link between mCx43 and K-ATP channels.

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