ROLE OF ANGIOTENSIN-II IN ACTIVATION OF THE JAK STAT PATHWAY INDUCED BY ACUTE PRESSURE-OVERLOAD IN THE RAT-HEART/

This study was designed to determine whether the JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) pathway is activated in cardiac hypertrophy induced in vivo by pressur e overload in rats and to demonstrate whether angiotensin II is involv ed in the activation of the JAK/STAT pathway. Acute pressure overload was produced by constricting the abdominal aorta of Wistar rats. Immun oprecipitation-Western blot analysis revealed that pressure overload a ctivated JAK1, JAK2, and Tyk2 as early as 5 minutes and that STAT1, ST AT2, and STAT3 were tyrosine-phosphorylated rapidly after exposure to the pressure overload. Phosphorylation of STAT1 and STAT2 peaked in th e early stage at 5 to 15 minutes, whereas that of STAT3 peaked in the late stage at 60 minutes. Gel mobility shift of the interferon gamma a ctivation site/interferon alpha-stimulating response element was obser ved immediately after the aortic banding, whereas the band of sis-indu cing element was shifted in the late stage at 60 minutes. Both cilazap ril (angiotensin II-converting enzyme inhibitor) and E4177 (angiotensi n II type 1 [AT(1)] receptor antagonist) significantly suppressed the phosphorylation of Tyk2 and partially inhibited the phosphorylation of JAK2, but neither affected JAK1. Coimmunoprecipitation of the AT(1) r eceptor with JAK2 or Tyk2 was clearly observed at 5 minutes and peaked at 15 minutes (20-fold the control value). These results indicate tha t the JAK/STAT pathway is activated by acute pressure overload in rats and that angiotensin II is involved in activating Tyk2, and partially activating JAK2, via the AT, receptor. Both angiotensin II-dependent and -independent pathways take part in activating the JAK/STAT pathway in the pressure-overloaded rat heart.