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 cellular growth associated with hypertension and in compensatory remodeling following myocardial infarction. The molecular signal transduction pathways that participate in these and other cellular actions in response to angiotensin II are presently being elucidated. The signal transducers and activators of transcription (STAT) pathway directly links cytokine and growth factor receptors with transcriptional activity. We provide evidence that the G protein-linked, angiotensin II, AT1-receptor 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-A. The EC50 of this response was 40 nM and Stat1 and Stat3 proteins were identified as components of the SIF complexes. Stat1 and Stat3 were tyrosine phosphorylated five-fold and three-fold, respectively, over control levels following angiotensin II treatment of cardiac myocytes. Phosphorylation of Stat1 and Stat3 proteins was rapid (5 min) and sustained (60 min). Jak2 was also tyrosine phosphorylated eight-fold by angiotensin II treatment, and phosphorylated Stat1 and Stat3 proteins co-immunoprecipitated with activated Jak2 kinase. Selective inhibition of Jak2 kinase with AG-490 blocked 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-immunoprecipitated with the AT1-receptor. These are the first data to demonstrate coupling of a G-protein coupled receptor, AT1, to the JAK-STAT pathway in primary cultured cardiac myocytes and suggest that this pathway may be involved in transcriptional regulation by angiotensin II.
McWhinney
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Sigfried and Janet Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, Pennsylvania, 17822, USA.
Hunt
R A
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Conrad
K M
KM
Dostal
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DE
Baker
K M
KM
D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000378:metabolism*; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D053614:Janus Kinase 2; D019808:Losartan; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013777:Tetrazoles / Q000494:pharmacology; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000378:metabolism; D020032:Tyrphostins
D004268:DNA-Binding Proteins; D007093:Imidazoles; D009570:Nitriles; D011518:Proto-Oncogene Proteins; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D011945:Receptors, Angiotensin; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494081:Stat1 protein, rat; C494088:Stat3 protein, rat; D013777:Tetrazoles; D015534:Trans-Activators; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D000804:Angiotensin II; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C066026:losartan carboxylic acid; D019808:Losartan