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PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
4
pubmed:dateCreated
2002-10-2
pubmed:abstractText
Although the serious cardiotoxicity of doxorubicin (DOX), a useful chemotherapeutic agent, limits the use of this agent, the mechanism of DOX-induced cardiomyopathy remains unclear. Since accumulating evidence suggests that activation of the renin-angiotensin system is involved in the development of various types of cardiovascular remodeling, we examined the role of angiotensin II (Ang II) in DOX-induced cardiotoxicity using Ang II type 1a receptor (AT1) knockout (KO) mice. To examine the role of AT1 in the acute effects of DOX, we injected a single 20 mg/kg dose of DOX into AT1KO mice, wild type (WT) mice and WT mice treated with an AT1 antagonist, RNH-6270; to examine the role of AT1 in the chronic effects of DOX, we injected mice of the same groups with 1 mg/kg DOX once a week for 12 weeks. Echocardiography revealed that cardiac function was significantly impaired in WT mice, but not in AT1KO mice or WT mice administered RNH-6270, by both acute and chronic DOX treatment. Histological analysis showed that DOX induced myofibrillar loss and increased the number of apoptotic cells in WT mice, but not in AT1KO mice or WT mice administered RNH-6270. Expression of the ANP gene was downregulated by DOX treatment in WT mice, and this alteration was attenuated in AT1KO mice and in RNH-6270-treated mice. We conclude that the AT1-mediated Ang II signaling pathway plays an important role in DOX-induced cardiac impairment, suggesting that an AT1 antagonist can be used to prevent DOX-induced cardiomyopathy.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jul
pubmed:issn
0916-9636
pubmed:author
pubmed:issnType
Print
pubmed:volume
25
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
597-603
pubmed:dateRevised
2010-11-18
pubmed:meshHeading
pubmed-meshheading:12358147-Angiotensin Receptor Antagonists, pubmed-meshheading:12358147-Animals, pubmed-meshheading:12358147-Antineoplastic Agents, pubmed-meshheading:12358147-Apoptosis, pubmed-meshheading:12358147-Cardiomyopathies, pubmed-meshheading:12358147-Cytoplasm, pubmed-meshheading:12358147-Doxorubicin, pubmed-meshheading:12358147-Gene Expression, pubmed-meshheading:12358147-Heart, pubmed-meshheading:12358147-Imidazoles, pubmed-meshheading:12358147-Male, pubmed-meshheading:12358147-Mice, pubmed-meshheading:12358147-Mice, Knockout, pubmed-meshheading:12358147-Myocardium, pubmed-meshheading:12358147-Myocytes, Cardiac, pubmed-meshheading:12358147-Myofibrils, pubmed-meshheading:12358147-Receptor, Angiotensin, Type 1, pubmed-meshheading:12358147-Receptors, Angiotensin, pubmed-meshheading:12358147-Reference Values, pubmed-meshheading:12358147-Tetrazoles, pubmed-meshheading:12358147-Vacuoles
pubmed:year
2002
pubmed:articleTitle
Angiotensin II type 1a receptor mediates doxorubicin-induced cardiomyopathy.
pubmed:affiliation
Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Japan.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't