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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Publications at this Location » Publication #145526
Title: ANTHRACYCLINE-INDUCED SUPRESSION OF GATA-4 TRANSCRIPTION FACTOR: IMPLICATION REGULATION OF CARDIAC MYOCYTE APOPTOSIS

Author
item KIM, YURI - HNRCA
item MA, AI-GUO - HNRCA
item KITTA, KAZUMI - NAT FOOD RES INST, JAPAN
item FITCH, SARAH - HNRCA
item IKEDA, TAKAYUKI - HOKKAIDO FOOD PROCESS RES
item IHARA, YOSHIHARU - HOKKAIDO FOOD PROCESS RES
item SIMON, AMY - NEMC
item EVANS, TODD - ALBERT EINSTEIN COLL MED
item SUZUKI, YUICHIRO - HNRCA

Submitted to: Molecular Pharmacology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/23/2002
Publication Date: 2/1/2003
Citation: KIM, Y., MA, A., KITTA, K., FITCH, S.N., IKEDA, T., IHARA, Y., SIMON, A.R., EVANS, T., SUZUKI, Y.J. ANTHRACYCLINE-INDUCED SUPRESSION OF GATA-4 TRANSCRIPTION FACTOR: IMPLICATION REGULATION OF CARDIAC MYOCYTE APOPTOSIS. MOLECULAR PHARMACOLOGY. 63:368-377,2003.

Interpretive Summary: Anthracyclines are effective anti-cancer drugs, but can induce heart damage as a side-effect. Understanding how these drugs damage the heart will help therapeutic strategies against cancer. Our study examined how the heart muscle cells get damaged by anthracyclines and identified that suppression of a protein called GATA-4 is involved. Inhibiting the suppression of GATA-4 by drugs or nutrients may reduce side effects by these anti-cancer drugs.

Technical Abstract: Anthracyclines are effective cancer chemotherapeutic agents but can induce serious cardiotoxicity. Understanding the mechanism of cardiac damage by these agents will help in development of better therapeutic strategies against cancer. The GATA-4 transcription factor is an important regulator of cardiac muscle cells. The present study demonstrates that anthracyclines can downregulate GATA-4 activity. Treatment of HL-1 cardiac muscle cells or isolated adult rat ventricular myocytes with anthracyclines such as daunorubicin and doxorubicin decreased the level of GATA-4 DNA-binding activity. The mechanism of decreased GATA-4 activity acts at the level of the GATA-4 gene, asanthracyclines caused significantly decreased levels of GATA-4 protein and mRNA. The rate of decline in GATA-4 transcript levels in the presence of actinomycin D was unaltered by anthracyclines, indicating that these agents may affect directly GATA-4 gene transcription. To determine if decreased GATA-4 levels are functionally related to cardiac muscle cell death that can be induced by anthracyclines, the ability of ectopic GATA factors to rescue anthracycline-induced apoptosis was tested. Adenovirus-mediated expression of either GATA-4 or GATA-6 was sufficient to attenuate the incidence of apoptosis. Further, suppression of GATA-4 DNA-binding activity by a dominant negative mutant of GATA-4 induced the apoptosis. These results suggest that the mechanism of anthracycline-induced cardiotoxicity may involve the downregulation of GATA-4 and the induction of apoptosis.