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

Authors:
Michela Pecoraro
Michela Pecoraro
School of Pharmacy
Lawrence | United States
Michele Ciccarelli
Michele Ciccarelli
University of Salerno
Fisciano | Italy
Antonella Fiordelisi
Antonella Fiordelisi
Federico II University
Prof. Guido Iaccarino, MD, PhD
Prof. Guido Iaccarino, MD, PhD
Federico II University of Naples
Full Professor of Applied Medical Science and Technology
Cardiology
Napoli, Campania | Italy
Aldo Pinto
Aldo Pinto
University of Salerno
Italy
Ada Popolo
Ada Popolo
University of Salerno
Italy

Int J Mol Sci 2018 Mar 7;19(3). Epub 2018 Mar 7.

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy.

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 K 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 Ca-ATPase (SERCAII) and a reduction in phospholamban (PLB) amounts in DZX+DOXO co-treated mice. A contemporary recovery of intracellular Ca-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.

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http://dx.doi.org/10.3390/ijms19030757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5877618PMC
March 2018
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1 Citation
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References

(Supplied by CrossRef)
Anthracycline-induced cardiotoxicity
Hrdina et al.
Acta Med. (Hrad. Kralove) 2000

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