Adrenomedullin inhibits doxorubicin-induced cultured rat cardiac myocyte apoptosis via a cAMP-dependent mechanism.
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.
Tokudome
Takeshi
T
Research Institute, National Cardiovascular Center, Suita, Osaka 565-8565, Japan.
Horio
Takeshi
T
Yoshihara
Fumiki
F
Suga
Shin-Ichi
S
Kawano
Yuhei
Y
Kohno
Masakazu
M
Kangawa
Kenji
K
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000111:Acetylcysteine / Q000494:pharmacology; D053607:Adrenomedullin; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002374:Catalase / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D053938:DNA Fragmentation; D004317:Doxorubicin / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009206:Myocardium / Q000166:cytology*; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides
D000970:Antineoplastic Agents; D000975:Antioxidants; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D007546:Isoquinolines; D010446:Peptide Fragments; D010455:Peptides; D011994:Recombinant Proteins; D013449:Sulfonamides; C058636:calcitonin gene-related peptide (8-37); D053607:Adrenomedullin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D004317:Doxorubicin; D000242:Cyclic AMP; D007770:L-Lactate Dehydrogenase; D002374:Catalase; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D000111:Acetylcysteine