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PMID:12193565

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Citation

Tokudome, T, Horio, T, Yoshihara, F, Suga, S, Kawano, Y, Kohno, M and Kangawa, K (2002) Adrenomedullin inhibits doxorubicin-induced cultured rat cardiac myocyte apoptosis via a cAMP-dependent mechanism. Endocrinology 143:3515-21

Abstract

We previously reported that adrenomedullin produced by cardiac myocytes acts as a local modulator in some cardiac disorders. However, the role of adrenomedullin (AM) in cardiomyocyte apoptosis remains to be clarified. The present study investigated the effect of AM on doxorubicin-induced cardiac myocyte apoptosis. Doxorubicin increased the number of cells with pyknotic nuclei and lactate dehydrogenase release, and AM dose-dependently (10(-10)-10(-8)6 M) inhibited these increases produced by doxorubicin. Treatment with AM also suppressed doxorubicin-induced DNA fragmentation and caspase-3 activation. 8-Bromo-cAMP, a cAMP analog, mimicked these antiapoptotic effects of AM. An AM/calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) and a protein kinase A inhibitor H89 attenuated the antiapoptotic effect of AM. CGRP-(8-37) and H89 had no apoptotic effect alone, but accelerated doxorubicin-induced apoptosis. Under serum-free conditions, AM secretion into the culture medium and expression of AM mRNA were significantly increased after treatment with doxorubicin. Hydrogen peroxide scavenger catalase and antioxidant N-acetyl-L-cysteine inhibited the doxorubicin-mediated increase in AM secretion and its gene expression. These results indicate that AM inhibits doxorubicin-induced cardiac myocyte apoptosis through a cAMP-dependent mechanism and suggest that augmented production of AM by doxorubicin has an endogenous antiapoptotic effect. AM, as an autocrine factor, may play a protective role against cardiomyocyte injury by doxorubicin.

Links

PubMed

Keywords

8-Bromo Cyclic Adenosine Monophosphate/pharmacology; Acetylcysteine/pharmacology; Adrenomedullin; Animals; Antineoplastic Agents/pharmacology; Antioxidants/pharmacology; Apoptosis/drug effects; Calcitonin Gene-Related Peptide/pharmacology; Cardiotonic Agents/pharmacology; Catalase/pharmacology; Cyclic AMP/pharmacology; Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors; DNA Fragmentation; Doxorubicin/pharmacology; Enzyme Inhibitors/pharmacology; Free Radical Scavengers/pharmacology; Humans; Isoquinolines/pharmacology; L-Lactate Dehydrogenase/metabolism; Myocardium/cytology; Peptide Fragments/pharmacology; Peptides/genetics; Peptides/pharmacology; Peptides/physiology; Peptides/secretion; Rats; Rats, Wistar; Receptors, Calcitonin Gene-Related Peptide/antagonists & inhibitors; Recombinant Proteins/pharmacology; Sulfonamides

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

RAT:ADML

involved_in

GO:0019933: cAMP-mediated signaling

ECO:0000270: expression pattern evidence used in manual assertion

P

Seeded From UniProt

complete

RAT:ADML

involved_in

GO:0009611: response to wounding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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