Doxorubicin selectively inhibits brain versus atrial natriuretic peptide gene expression in cultured neonatal rat myocytes.
Doxorubicin is an antineoplastic agent with significant cardiotoxicity. We examined the effects of this agent on the expression of the natriuretic peptide (NP) genes in cultured neonatal rat atrial myocytes. Doxorubicin suppressed NP secretion, steady-state NP mRNA levels, and NP gene promoter activity. In each instance, brain NP (BNP) proved to be more sensitive than atrial NP (ANP) to the inhibitory effects of the drug. ICRF-187 and probucol reversed the inhibition by doxorubicin of ANP mRNA accumulation and ANP gene promoter activity while exerting no effect on BNP mRNA levels or promoter activity. This represents the first identification of the NP genes as targets of doxorubicin toxicity in the myocardial cell. This inhibition operates predominantly at a transcriptional locus and has more potent effects on BNP versus ANP secretion/gene expression. Measurement of BNP secretion/gene expression may provide a sensitive marker of early doxorubicin cardiotoxicity.
Chen
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Metabolic Research Unit and Department of Medicine, University of California at San Francisco, 94143, USA.
Garami
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Gardner
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DG
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000633:toxicity*; D009320:Atrial Natriuretic Factor / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D002317:Cardiovascular Agents / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003609:Dactinomycin / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015870:Gene Expression / Q000187:drug effects*; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D020097:Natriuretic Peptide, Brain / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D011341:Probucol / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011929:Razoxane / Q000494:pharmacology; D014162:Transfection
D000924:Anticholesteremic Agents; D000970:Antineoplastic Agents; D002317:Cardiovascular Agents; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D020097:Natriuretic Peptide, Brain; D003609:Dactinomycin; D011929:Razoxane; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; D011341:Probucol