Cardiotrophin-1 increases angiotensinogen mRNA in rat cardiac myocytes through STAT3: an autocrine loop for hypertrophy

J Fukuzawa, GW Booz, RA Hunt, N Shimizu… - …, 2000 - Am Heart Assoc
J Fukuzawa, GW Booz, RA Hunt, N Shimizu, V Karoor, KM Baker, DE Dostal
Hypertension, 2000Am Heart Assoc
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 …
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.
Am Heart Assoc