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Doxorubicin cardiomyopathy-induced inflammation and apoptosis are attenuated by gene deletion of the kinin B1 receptor
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Dirk Westermann
Published/Copyright:
May 15, 2008
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.
Received: 2007-10-31
Accepted: 2008-1-5
Published Online: 2008-05-15
Published in Print: 2008-06-01
©2008 by Walter de Gruyter Berlin New York
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Keywords for this article
bradykinin;
cardiac apoptosis;
cardiac inflammation;
doxorubicin cardiomyopathy
Articles in the same Issue
- Editorial
- Kallikreins and kallikrein-related peptidases
- Guest Editorial
- The 2nd International Symposium on Kallikreins and Kallikrein-Related Peptidases (ISK 2007) and the Commemorative Gold Medal of the E.K. Frey–E. Werle Foundation of the Henning L. Voigt Family
- Highlight: Kallikrein, kinins and kallikrein-related peptidases
- Structures and specificity of the human kallikrein-related peptidases KLK 4, 5, 6, and 7
- Development of peptides specifically modulating the activity of KLK2 and KLK3
- Kallikreins and proteinase-mediated signaling: proteinase-activated receptors (PARs) and the pathophysiology of inflammatory diseases and cancer
- Prostatic trypsin-like kallikrein-related peptidases (KLKs) and other prostate-expressed tryptic proteinases as regulators of signalling via proteinase-activated receptors (PARs)
- Human tissue kallikreins as promiscuous modulators of homeostatic skin barrier functions
- A potential role for tissue kallikrein-related peptidases in human cervico-vaginal physiology
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- Tissue kallikrein and kinin infusion promotes neovascularization in limb ischemia
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