Angiotensin II-stimulated induction of sis-inducing factor is mediated by pertussis toxin-insensitive G(q) proteins in cardiac myocytes.
The Janus kinase-signal transducers and activators of transcription (JAK-STAT) pathway is stimulated by angiotensin II (Ang II) via the type 1 receptor after acute pressure overload in the heart. The purpose of this study was to determine whether activation of the JAK-STAT pathway by Ang II is dependent on G proteins. Ang II (100 nmol/L for 120 minutes) caused formation of sis-inducing factor (SIF) complexes and tyrosine phosphorylation of STAT proteins in neonatal rat ventricular myocytes. The percentage of change in Ang II-stimulated SIF induction was not affected by pertussis toxin (PTX) or GP antagonist-2A, compounds that inhibit activation of G(i) and G(o) proteins. In contrast, GP antagonist-2A, a peptide that selectively inhibits activation of G(q) proteins, completely abolished Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation. Pretreatment of cardiac myocytes with U73122, an inhibitor of phosphatidylinositol-specific phospholipase C (PLC) activity, decreased Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation in a dose-dependent manner. Chelation of intracellular Ca(2+) with BAPTA-AM did not alter Ang II-stimulated SIF induction. In contrast, pretreatment of cardiac myocytes with Ro-31-8220, a potent and specific inhibitor of protein kinase C (PKC), decreased Ang II-stimulated SIF induction in a dose-dependent manner. Ang II-stimulated SIF induction was abolished in cardiac myocytes after downregulation of PKC by treatment with PMA. From these data, we conclude that Ang II-stimulated SIF induction and STAT3 tyrosine phosphorylation is mediated by PTX-insensitive G proteins through a G(q)-PLC-PKC-mediated pathway in neonatal rat ventricular myocytes.
Hunt
R A
RA
Pennsylvania State University College of Medicine, Henry Hood MD Research Program, Sigfried and Janet Weis Center for Research, 100 North Academy Ave, Danville, Pa, USA.
Bhat
G J
GJ
Baker
K M
KM
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D004268:DNA-Binding Proteins / Q000187:drug effects* / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000502:physiology*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D037342:Pertussis Toxin; D010716:Phosphatidylinositols / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects*; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D004268:DNA-Binding Proteins; D010716:Phosphatidylinositols; D015534:Trans-Activators; D010566:Virulence Factors, Bordetella; D000804:Angiotensin II; D037342:Pertussis Toxin; D011505:Protein-Tyrosine Kinases; D019204:GTP-Binding Proteins