BIPHASIC ACTIVATION OF THE JAK STAT PATHWAY BY ANGIOTENSIN-II IN RAT CARDIOMYOCYTES/

This study was designed to demonstrate the characteristic pattern of a ngiotensin II-induced JAK/STAT (indicating just another kinase/signal transducer and activator of transcription) activation in cultured rat cardiomyocytes by comparing it with leukemia inhibitory factor (LIF)-i nduced activation. Angiotensin II (10(-7) mol/L) induced rapid phospho rylation of JAK2 and Tyk2, but not JAK1, and phosphorylated STAT1 and STAT2, but not STAT3, in the early stage up to 30 minutes. The time co urse of JAK/STAT activation by angiotensin II was apparently slower th an that by LIF. Interestingly, angiotensin II phosphorylated STAT3 and rephosphorylated STAT1 in the late stage at 120 minutes. We also foun d that angiotensin II induced the formation of interferon-stimulating gene factor (ISGF) complexes biphasically, in the early stage at 15 to 30 minutes and in the late stage at 120 minutes, and that angiotensin II induced delayed activation of the sis-inducing factor (SIF) comple x at 120 minutes. Formation of ISGF and SIF complexes in response to a ngiotensin II paralleled the phosphorylation pattern of STAT1 and STAT 3 and was quite different from those obtained in response to LIF. The phosphorylation of STAT1 was suppressed by pretreatment with the angio tensin II type-1 (AT,) receptor antagonist CV11974, but the delayed ad dition of CV11974 failed to suppress phosphorylation oi STAT3 at 120 m inutes, In conclusion, angiotensin II-induced JAK/STAT activation in r at cardiomyocytes is biphasic and entirely different from LIF-induced activation.