Signal transducer and activator of transcription 3 in the heart transduces not only a hypertrophic signal but a protective signal against doxorubicin-induced cardiomyopathy.
The signal transducer and activator of transcription (STAT) 3, a transcriptional factor downstream of several cytokines, is activated by Janus kinase families and plays a pivotal role in cardiac hypertrophy through gp130. To determine the physiological significance of STAT3 in vivo, transgenic mice with cardiac-specific overexpression of the Stat3 gene (STAT3-TG) were generated. STAT3-TG manifested myocardial hypertrophy at 12 wk of age with increased expression of the atrial natriuretic factor (ANF), beta-myosin heavy chain (MHC), and cardiotrophin (CT)-1 genes. The animals were injected i.p. with 15 mg/kg doxorubicin (Dox), an antineoplastic drug with restricted use because of its cardiotoxicity. The survival rates after 10 days were 25% (5/20) for control littermates (WT), but 80% (16/20) for STAT3-TG (P < 0.01). WT showed increased expression of beta-MHC and ANF mRNAs in the hearts 1 day after Dox treatment; this expression peaked at 3 days, suggesting that the WT suffered from congestive heart failure. Although the expression of these mRNAs was elevated in STAT3-TG hearts before Dox treatment, no additional increase was observed after the treatment. Dox administration significantly reduced the expression of the cardiac alpha-actin and Stat3 genes in WT hearts but not in STAT3-TG. These results provide direct evidence that STAT3 transduces not only a hypertrophic signal but also a protective signal against Dox-induced cardiomyopathy by inhibiting reduction of cardiac contractile genes and inducing cardiac protective factors.
Kunisada
K
K
Department of Molecular Medicine, Osaka University Medical School, Osaka 565-0871 Japan.
Negoro
S
S
Tone
E
E
Funamoto
M
M
Osugi
T
T
Yamada
S
S
Okabe
M
M
Kishimoto
T
T
Yamauchi-Takihara
K
K
D000199:Actins / Q000235:genetics; D000818:Animals; D000970:Antineoplastic Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology; D009320:Atrial Natriuretic Factor / Q000235:genetics; D006332:Cardiomegaly / Q000235:genetics*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000401:mortality; D016207:Cytokines / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004317:Doxorubicin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005786:Gene Expression Regulation; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000473:pathology; D018995:Myosin Heavy Chains / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D015534:Trans-Activators / Q000235:genetics*
D000199:Actins; D000970:Antineoplastic Agents; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D004317:Doxorubicin; D009320:Atrial Natriuretic Factor; C092073:cardiotrophin 1; D018995:Myosin Heavy Chains