Angiotensin II-induced Egr-1 expression is suppressed by peroxisome proliferator-activated receptor-γ ligand 15d-PGJ₂ in macrophages.

BACKGROUND/AIMS Angiotensin II (Ang II) plays a critical role in regulating vascular inflammatory diseases, such as atherosclerosis and hypertension. Early growth response-1 (Egr-1) is an immediate early gene that acts as a master switch for the inflammatory response. However, the role of Ang II in regulating Egr-1 expression in macrophages, and the effect of peroxisome proliferators-activated receptor-γ (PPAR-γ) ligand 15d-PGJ2 in this process remain to be investigated. METHODS AND RESULTS We showed that Ang II significantly up-regulated the expression of Egr-1 in RAW264.7 macrophages, and this effect was markedly attenuated by Eprosartan (an AT1R blocker), SP600125 (a JNK-specific inhibitor) and PD98059 (an ERK-specific inhibitor). Moreover, treatment of macrophages with 15d-PGJ2, a natural PPAR-γ ligand, significantly reduced Ang II-induced expression of Egr-1 and its inflammatory gene targets (IL-1β, TNF-α, TGF-β, MCP-1 and ICAM-1) through PPAR-γ activation and ROS formation. In addition, 15d-PGJ2 treatment markedly inhibited Ang II-induced macrophage migration and proliferation. CONCLUSIONS This study for the first time demonstrates that Ang II can induce the expression of Egr-1 via AT1R/JNK and ERK signaling pathways. Activation of PPAR-γ by 15d-PGJ2 suppresses Egr-1-mediated proinflammatory response, and may be a novel therapeutic strategy for treatment of vascular inflammatory diseases.