title: Protective effects of endothelin receptor A and B inhibitors against doxorubicin-induced cardiomyopathy.
abstract: The clinical efficiency of the highly potent antitumor agent doxorubicin is limited by cardiotoxic effects. In a murine doxorubicin cardiotoxicity model, increased endothelin-1 (ET-1) expression and cardioprotective effects of the dual ET-1 blocker bosentan were demonstrated. To date it is unclear if combined blocking of endothelin A/B receptors is necessary or whether selective inhibition of one of the ET-1 receptors is sufficient for the observed cardioprotection. Therefore, we investigated the impact of dual (bosentan) and single endothelin receptor antagonism through sitaxentan (receptor A blocker) or BQ788 (receptor B blocker) in a murine doxorubicin cardiotoxicity model (C57BL/6N). Simultaneous administration of each endothelin receptor antagonist (ERA) with doxorubicin resulted in a significantly improved hemodynamic performance in comparison to the impaired cardiac function in control mice with bosentan being most effective but closely followed by sitaxentan and also BQ788. This cardioprotection was not caused by diminished doxorubicin levels in heart since the doxorubicin content in cardiac tissue was not altered by ERAs significantly. However, whole transcript expression profiling showed partly different effects of the ERAs on doxorubicin-modulated cardiac gene expression of genes involved in signal transduction (e.g. Stat3, Pim1, Akt1, Plcb2), fibrosis (e.g. Myl4), energy production (e.g. Ant1) or oxidative stress (e.g. Aox1). Furthermore, doxorubicin-mediated gene regulations were verified in the murine cardiomyocyte model HL-1 showing partly reversed expression patterns after co-administration of the ERAs. In summary, our results demonstrate strong cardioprotective effects of blocking ET-1 receptors against the doxorubicin-related cardiomyopathy and provide evidence to potential underlying signaling pathways.
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Matthias
authors: M
authors: Schwebe
authors: Institute of Functional Genomics, University Medicine, Greifswald, Germany.
authors: Sabine
authors: S
authors: Ameling
authors: Institute of Functional Genomics, University Medicine, Greifswald, Germany.
authors: Elke
authors: E
authors: Hammer
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Judith V
authors: JV
authors: Monzel
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Karina
authors: K
authors: Bonitz
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Susanne
authors: S
authors: Budde
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Kathleen
authors: K
authors: Schult
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Stefan
authors: S
authors: Oswald
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Eberhard
authors: E
authors: Scheuch
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Markus
authors: M
authors: Grube
authors: Institute of Cardiology, University Medicine, Greifswald, Germany.
authors: Axel
authors: A
authors: Poesch
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Thomas
authors: T
authors: Budde
authors: Institute of Pulmology, University Medicine, Greifswald, Germany.
authors: Ralf
authors: R
authors: Ewert
authors: Clinic of Neurosurgery, University Medicine, Greifswald, Germany.
authors: Henry W S
authors: HW
authors: Schroeder
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany.
authors: Heyo K
authors: HK
authors: Kroemer
authors: Center of Drug Absorption and Transport (C_DAT), Institute of Pharmacology, University Medicine, Greifswald, Germany. Electronic address: sbien@uni-greifswald.de.
authors: Sandra
authors: S
authors: Bien-Möller
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced / Q000517:prevention & control*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004317:Doxorubicin / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044022:Receptor, Endothelin A / Q000187:drug effects*; D044023:Receptor, Endothelin B / Q000187:drug effects*
chemical_list: D000903:Antibiotics, Antineoplastic; D002316:Cardiotonic Agents; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D004317:Doxorubicin
keywords: Cardiomyopathy; Doxorubicin; Endothelin