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(Hypertension. 2000;35:1191.)
© 2000 American Heart Association, Inc.

Cooper Lecture

Cardiotrophin-1 Increases Angiotensinogen mRNA in Rat Cardiac Myocytes Through STAT3

An Autocrine Loop for Hypertrophy

Jun Fukuzawa; George W. Booz; Rachel A. Hunt; Noriko Shimizu; Vijaya Karoor; Kenneth M. Baker; David E. Dostal

From the Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine (J.F., D.E.D., G.W.B., K.M.B.), Temple, Tex; and the Henry Hood Research Program, Sigfried and Janet Weis Center for Research, Pennsylvania State University College of Medicine (R.A.H., V.K., N.S.), Danville, Penn.

Correspondence to Kenneth M. Baker, MD, Cardiovascular Research Institute, Division of Molecular Cardiology, The Texas A&M University System Health Science Center, College of Medicine, 1901 S 1st St, Bldg 162, Temple, TX 76504. E-mail kbaker{at}medicine.tamu.edu

Abstract—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.

Key Words: angiotensinogen • gene expression • promoter regions • motifs • Janus kinases • STAT pathway • cardiac myocyte

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