title: Doxorubicin-Mediated Cardiotoxicity: Role of Mitochondrial Connexin 43.
abstract: Doxorubicin is the highly effective anthracycline, but its clinical use is limited by cardiotoxicity and consequent dysfunction. It has been proposed that the etiology of this is related to mitochondrial dysfunction. Connexin 43 (Cx43), the principal protein building block of cardiac gap junctions and hemichannels, plays an important role in cardioprotection. Recent reports confirmed the presence of Cx43 in the mitochondria as well. In this study, the role of mitochondrial Cx43 was evaluated 3 or 6 h after Doxorubicin administration to the rat heart cell line H9c2. Pharmacological inhibition of Hsp90 demonstrated that the mitochondrial Cx43 conferred cardioprotection by reducing cytosolic and mitochondrial reactive oxygen species production, mitochondrial calcium overload and mitochondrial membrane depolarization and cytochrome c release. In conclusion, our study demonstrates that Cx43 plays an important role in the protection of cardiac cells from Doxorubicin-induced toxicity.
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Pecoraro
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Rosalinda
authors.initials: R
authors.lastname: Sorrentino
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Franceschelli
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Mariagiovanna
authors.initials: M
authors.lastname: Del Pizzo
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.affiliation: Department of Pharmacy, School of Pharmacy, University of Salerno, Via Giovanni Paolo II 132, 84084, Fisciano, SA, Italy. apopolo@unisa.it.
authors.forename: Ada
authors.initials: A
authors.lastname: Popolo
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D020013:Calcium Signaling; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism; D002460:Cell Line; D018031:Connexin 43 / Q000378:metabolism*; D045304:Cytochromes c / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000633:toxicity*; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D021381:Protein Transport; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000903:Antibiotics, Antineoplastic; D018031:Connexin 43; C580592:Gja1 protein, rat; D018841:HSP90 Heat-Shock Proteins; D017382:Reactive Oxygen Species; D004317:Doxorubicin; D045304:Cytochromes c
keywords: Connexin 43; Doxorubicin; Hsp90; Mitochondria