The endothelin receptor blocker bosentan inhibits doxorubicin-induced cardiomyopathy.
Doxorubicin is a frequently used anticancer drug, but its therapeutic benefit is limited by acute and chronic cardiotoxicity, often leading to heart failure. The mechanisms underlying doxorubicin-induced cardiotoxicity remain unclear. It was previously shown in men that doxorubicin leads to increased endothelin-1 plasma levels. In addition, cardiac-specific overexpression of endothelin-1 in mice resulted in a cardiomyopathy resembling the phenotype following doxorubicin administration. We therefore hypothesized that endothelin-1 is involved in the pathogenesis of doxorubicin cardiotoxicity. In mice (C57Bl/10), we found that doxorubicin (20 mg/kg body weight, i.p.) impaired cardiac function with decreased ejection fraction, diminished cardiac output, and decreased end-systolic pressure points recorded by a microconductance catheter. This impaired function was accompanied by the up-regulation of endothelin-1 expression on mRNA and protein level. In vitro investigations confirmed the regulation of endothelin-1 by doxorubicin and indicated that the doxorubicin-mediated increase of endothelin-1 expression involves epidermal growth factor receptor signaling via the MEK1/2-ERK1/2 cascade, which was further confirmed by immunoblotting studies in the left ventricle of treated animals. Pretreatment of mice with the endothelin receptor antagonist bosentan (100 mg/kg body weight, p.o.) strikingly inhibited doxorubicin-induced cardiotoxicity with preserved indices of contractility. Moreover, bosentan pretreatment resulted in reduced tumor necrosis factor-alpha content, lipid peroxidation, and Bax expression, as well as increased GATA-4 expression. Thus, endothelin-1 plays a key role in mediating the cardiotoxic effects of doxorubicin and its inhibition may be of therapeutic benefit for patients receiving doxorubicin.
Bien
Sandra
S
Department of Pharmacology, Ernst Moritz Arndt University, Greifswald, Germany.
Riad
Alexander
A
Ritter
Christoph A
CA
Gratz
Matthias
M
Olshausen
Florian
F
Westermann
Dirk
D
Grube
Markus
M
Krieg
Thomas
T
Ciecholewski
Sabine
S
Felix
Stephan B
SB
Staudt
Alexander
A
Schultheiss
Heinz-Peter
HP
Ewert
Ralf
R
Völker
Uwe
U
Tschöpe
Carsten
C
Kroemer
Heyo K
HK
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D000077300:Bosentan; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000517:prevention & control; D004317:Doxorubicin / Q000633:toxicity*; D019332:Endothelin-1 / Q000096:biosynthesis; D066246:ErbB Receptors / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D050991:GATA4 Transcription Factor / Q000032:analysis; D015227:Lipid Peroxidation; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D048370:MAP Kinase Kinase 2 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D013449:Sulfonamides / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D019332:Endothelin-1; D050991:GATA4 Transcription Factor; D013449:Sulfonamides; D014409:Tumor Necrosis Factor-alpha; D004317:Doxorubicin; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482127:Map2k1 protein, mouse; C482129:Map2k2 protein, mouse; D000077300:Bosentan