Angiotensin II Regulates Th1 T Cell Differentiation Through Angiotensin II Type 1 Receptor-PKA-Mediated Activation of Proteasome

Background/Aims: Naive CD4(+) T cells differentiate into T helper cells (Th1 and Th2) that play an essential role in the cardiovascular diseases. However, the molecular mechanism by which angiotensin II (Ang II) promotes Th1 differentiation remains unclear. The aim of this study was to determine whether the Ang II-induced Thl differentiation regulated by ubiquitin-proteasome system (UPS). Methods: Jurkat cells were treated with Ang II (100 nM) in the presence or absence of different inhibitors. The gene mRNA levels were detected by real-time quantitative PCR analysis. The protein levels were measured by ELISA assay or Western blot analysis, respectively. Results:_Ang II treatment significantly induced a shift from Th0 to Thl cell differentiation, which was markedly blocked by angiotensin II type 1 receptor (AT1R) inhibitor Losartan (LST). Moreover, Ang II significantly increased the activities and the expression of proteasome catalytic subunits (beta 1, beta 1i. beta 2i and beta 5i) in a dose- and time-dependent manner. However, Ang II-induced proteasome activities were remarkably abrogated by LST and PKA inhibitor H-89. Mechanistically, Ang II-induced Thl differentiation was at least in part through proteasome-mediated degradation of I kappa B alpha and MKP-1 and activation of STAT1 and NF-kappa B. Conclusions: This study for the first time demonstrates that Ang II activates AT1R-PKA-proteasome pathway, which promotes degradation of I kappa B alpha and MKP-1 and activation of STAT1 and NF-kappa B thereby leading to Thl differentiation. Thus, inhibition of proteasome activation might be a potential therapeutic target for Th1-mediated diseases. (C) 2018 The Author(s) Published by S Karger AG, Basel