Biphasic Activation of the JAK/STAT Pathway by Angiotensin II in Rat Cardiomyocytes

From the Cardiopulmonary Division (H.K., K.F., J.P., S.M., M.S., T.T., S.O.), Department of Internal Medicine, and the Department of Emergency Medicine (S.H.), Keio University, Tokyo, Japan.

Abstract—This study was designed to demonstrate the characteristic pattern of angiotensin 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)-induced activation. Angiotensin II (10^-7 mol/L) induced rapid phosphorylation 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 course of JAK/STAT activation by angiotensin II was apparently slower than that by LIF. Interestingly, angiotensin II phosphorylated STAT3 and rephosphorylated STAT1 in the late stage at 120 minutes. We also found 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) complex at 120 minutes. Formation of ISGF and SIF complexes in response to angiotensin II paralleled the phosphorylation pattern of STAT1 and STAT3 and was quite different from those obtained in response to LIF. The phosphorylation of STAT1 was suppressed by pretreatment with the angiotensin II type-1 (AT₁) receptor antagonist CV11974, but the delayed addition of CV11974 failed to suppress phosphorylation of STAT3 at 120 minutes. In conclusion, angiotensin II–induced JAK/STAT activation in rat cardiomyocytes is biphasic and entirely different from LIF-induced activation.

Key Words: angiotensin II • cardiomyocyte • cardiac hypertrophy • JAK/STAT pathway • signal transduction

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