title: Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor.
abstract: Clinical use of the anthracycline doxorubicin (DOX) is limited by its cardiotoxic effects, which are attributed to the induction of apoptosis. To elucidate the possible role of the kinin B1 receptor (B1R) during the development of DOX cardiomyopathy, we studied B1R knockout mice (B1R(-/-)) by investigating cardiac inflammation and apoptosis after induction of DOX-induced cardiomyopathy. DOX control mice showed cardiac dysfunction measured by pressure-volume loops in vivo. This was associated with a reduced activation state of AKT, as well as an increased bax/bcl2 ratio in Western blots, indicating cardiac apoptosis. Furthermore, mRNA levels of the proinflammatory cytokine interleukin 6 were increased in the cardiac tissue. In DOX B1R(-/-) mice, cardiac dysfunction was improved compared to DOX control mice, which was associated with normalization of the bax/bcl-2 ratio and interleukin 6, as well as AKT activation state. These findings suggest that B1R is detrimental in DOX cardiomyopathy in that it mediates the inflammatory response and apoptosis. These insights might have useful implications for future studies utilizing B1R antagonists for treatment of human DOX cardiomyopathy.
authors.affiliation: Charité-Universitätsmedizin Berlin, Department of Cardiology and Pneumology, Campus Benjamin Franklin, D-12200 Berlin, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Westermann
authors.forename: Olga
authors.initials: O
authors.lastname: Lettau
authors.forename: Meike
authors.initials: M
authors.lastname: Sobirey
authors.forename: Alexander
authors.initials: A
authors.lastname: Riad
authors.forename: Michael
authors.initials: M
authors.lastname: Bader
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000150:complications / Q000209:etiology / Q000378:metabolism* / Q000473:pathology*; D004317:Doxorubicin / Q000009:adverse effects*; D017353:Gene Deletion; D006439:Hemodynamics; D007249:Inflammation / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D043783:Receptor, Bradykinin B1 / Q000235:genetics* / Q000378:metabolism*; D043782:Receptor, Bradykinin B2 / Q000378:metabolism
chemical_list: D043783:Receptor, Bradykinin B1; D043782:Receptor, Bradykinin B2; D004317:Doxorubicin; D051057:Proto-Oncogene Proteins c-akt