Linked Life Data

15733908

Source:http://linkedlifedata.com/resource/pubmed/id/15733908

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
3
pubmed:dateCreated
2005-2-28
pubmed:abstractText
During chemotherapy with anthracyclines, attenuated neuregulin signaling by the erbB2 receptor inactivating antibody Trastuzumab enhances the heart failure risk. We compared the effects of attenuated neuregulin/erbB signaling and of daunorubicin on splicing of the Bcl-x gene and on mitochondrial activation of apoptosis in cardiomyocytes. Attenuating erbB signals in cultured neonatal rat cardiomyocytes by the erbB2 antagonist tyrphostin AG825, by the erbB1/4 antagonist AG1478 or by antisense-induced lowering of erbB2 receptors resulted in an augmented Bcl-xS/Bcl-xL ratio, mitochondrial release of cytochrome c, activation of caspase 9 and caspase 3, and nucleosome-sized DNA fragmentation. A similar DNA fragmentation and caspase 3 activation was induced by TNF-alpha, but without Bcl-xS/Bcl-xL increase, cytochrome c release or caspase 9 activation. A BH4-domain containing HIV TAT fusion protein added to cardiomyocytes under attenuated erbB signaling lowered the enhanced Bcl-xS/Bcl-xL ratio, the cytochrome c release, the caspase 3 activation and the DNA fragmentation, while apoptosis was not modified by the fusion protein in TNF-alpha treated cardiomyocytes. Enhancement of Bcl-xS/Bcl-xL by reducing Bcl-xL via siRNA transfection mimicked the mitochondrial apoptotic activation due to erbB signal attenuation. Daunorubicin also caused Bcl-xS/Bcl-xL enhancement and mitochondrial apoptotic activation in cultured cardiomyocytes; this was attenuated by BH4-fusion protein or by neuregulin-1 and augmented by siRNA-mediated Bcl-xL lowering. We conclude that activation of mitochondrial apoptosis due to altered Bcl-x splicing contributes as a common mechanism of anthracyclines and erbB signal attenuation to the enhanced heart failure risk under this combination.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Mar
pubmed:issn
0022-2828
pubmed:author
pubmed:issnType
Print
pubmed:volume
38
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
485-93
pubmed:dateRevised
2006-11-15
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Apoptosis-modulating interaction of the neuregulin/erbB pathway with anthracyclines in regulating Bcl-xS and Bcl-xL in cardiomyocytes.
pubmed:affiliation
Institute of Pathophysiology, Martin Luther University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097 Halle, Germany. susanne.rohrbach@medizin.uni-halle.de
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't