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Int. J. Mol. Sci. 2018, 19(3), 757; doi:10.3390/ijms19030757

Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy
Department of Medicine and Surgery, University of Salerno, 84084 Baronissi, Italy
Department of Advanced Biomedical Sciences, Federico II University, 80138 Naples, Italy
Author to whom correspondence should be addressed.
Received: 22 January 2018 / Revised: 1 March 2018 / Accepted: 5 March 2018 / Published: 7 March 2018
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Doxorubicin (DOXO) administration induces alterations in Connexin 43 (Cx43) expression and localization, thus, inducing alterations in chemical and electrical signal transmission between cardiomyocytes and in intracellular calcium homeostasis even evident after a single administration. This study was designed to evaluate if Diazoxide (DZX), a specific opener of mitochondrial KATP channels widely used for its cardioprotective effects, can fight DOXO-induced cardiotoxicity in a short-time mouse model. DZX (20 mg/kg i.p.) was administered 30 min before DOXO (10 mg/kg i.p.) in C57BL/6j female mice for 1–3 or seven days once every other day. A recovery of cardiac parameters, evaluated by Echocardiography, were observed in DZX+DOXO co-treated mice. Western blot analysis performed on heart lysates showed an increase in sarco/endoplasmic reticulum Ca2+-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca2+-signal, detected spectrofluorometrically by means of FURA-2AM, was observed in these mice. Cx43 expression and localization, analyzed by Western blot and confirmed by immunofluorescence analysis, showed that DZX co-treatement increases Cx43 amount both on sarcoplasmic membrane and on mitochondria. In conclusion, our data demonstrate that, in a short-time mouse model of DOXO-induced cardiotoxicity, DZX exerts its cardioprotective effects also by enhancing the amount Cx43. View Full-Text
Keywords: diazoxide; doxorubicin; connexin 43; calcium homeostasis diazoxide; doxorubicin; connexin 43; calcium homeostasis

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Pecoraro, M.; Ciccarelli, M.; Fiordelisi, A.; Iaccarino, G.; Pinto, A.; Popolo, A. Diazoxide Improves Mitochondrial Connexin 43 Expression in a Mouse Model of Doxorubicin-Induced Cardiotoxicity. Int. J. Mol. Sci. 2018, 19, 757.

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