THE TYPE-I ANGIOTENSIN-II RECEPTOR COUPLES TO STAT1 AND STAT3 ACTIVATION THROUGH JAK2 KINASE IN NEONATAL RAT CARDIAC MYOCYTES

The octapeptide, angiotensin II, has a modulatory role on cardiac cell ular growth associated with hypertension and in compensatory remodelin g following myocardial infarction, The molecular signal transduction p athways that participate in these and other cellular actions in respon se to angiotensin II are presently being elucidated. The signal transd ucers and activators of transcription (STAT) pathway directly links cy tokine and growth factor receptors with transcriptional activity, We p rovide evidence that the G protein-linked, angiotensin II, AT(1)-recep tor couples to activation of the STAT pathway in neonatal rat cardiac myocytes. Angiotensin II induces primarily sis-inducing factor (SIF) B and to a lesser extent SIF-C and SIF-X. The EC50 of this response was 40 nM and Stat1 and Stat3 proteins were identified as components of t he SIF complexes. Stat1 and Stat3 were tyrosine phosphorylated five-fo ld and three-fold, respectively, over control levels following angiote nsin II treatment of cardiac myocytes. Phosphorylation of Stat1 and St at3 proteins was rapid (5 min) and sustained (60 min). Jak2 was also t yrosine phosphorylated eight-fold by angiotensin II treatment, and pho sphorylated Stat1 and Stat3 proteins co-immunoprecipitated with activa ted Jak2 kinase. Selective inhibition of Jak2 kinase with AG-490 block ed formation of angiotensin II induced SIF complexes, suggesting that Jak2 kinase is required for cardiomyocyte SIF induction. In addition, Jak2, Stat1 and Stat3 proteins co-immnunoprecipitated with the AT(1)-r eceptor. These are the first data to demonstrate coupling of a G-prote in coupled receptor, AT(1), to the JAK-STAT pathway in primary culture d cardiac myocytes and suggest that this pathway map be involved in tr anscriptional regulation by angiotensin II. (C) 1997 Academic Press Li mited.