Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3 : an autocrine loop for hypertrophy.
-Cardiotrophin-1, an interleukin-6-related cytokine, stimulates the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway and induces cardiac myocyte hypertrophy. In this study, we demonstrate that cardiotrophin-1 induces cardiac myocyte hypertrophy in part by upregulation of a local renin-angiotensin system through the JAK/STAT pathway. We found that cardiotrophin-1 increased angiotensinogen mRNA expression in cardiac myocytes via STAT3 activation. Tyrosine phosphorylation of STAT3 by cardiotrophin-1 treatment resulted in STAT3 homodimer binding to the St-domain in the angiotensinogen gene promoter, which lead to promoter activation in a transient transfection assay. Cardiotrophin-1-induced STAT3 tyrosine phosphorylation and binding to the St-domain were suppressed by AG490, a specific JAK2 inhibitor, which also attenuated cardiotrophin-1-stimulated angiotensinogen promoter activity. Cardiotrophin-1 did not activate the angiotensinogen gene promoter that contained a substitution mutation within the St-domain. Finally, losartan, an angiotensin II type 1 receptor antagonist, significantly attenuated cardiotrophin-1-induced hypertrophy of neonatal rat cardiac myocytes. Angiotensin II is known to induce cardiac myocyte hypertrophy by activating the G-protein-coupled angiotensin II type 1 receptor. Our results suggest that upregulation of angiotensinogen and angiotensin II production contribute to cardiotrophin-1-induced cardiac myocyte hypertrophy and emphasize an important interaction between G-protein-coupled and cytokine receptors.
Fukuzawa
J
J
Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, Temple, Texas 76504, USA.
Booz
G W
GW
Hunt
R A
RA
Shimizu
N
N
Karoor
V
V
Baker
K M
KM
Dostal
D E
DE
D057911:Angiotensin Receptor Antagonists; D000808:Angiotensinogen / Q000235:genetics*; D000818:Animals; D019898:Autocrine Communication; D006332:Cardiomegaly / Q000209:etiology / Q000517:prevention & control; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; D015534:Trans-Activators / Q000378:metabolism / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D057911:Angiotensin Receptor Antagonists; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D050796:STAT3 Transcription Factor; C494088:Stat3 protein, rat; D015534:Trans-Activators; D000808:Angiotensinogen; D014443:Tyrosine; C092073:cardiotrophin 1