Preventive Effect of Caffeic Acid Phenethyl Ester, an Active Component of Propolis, against TNF-α-Induced Endothelial Dysfunction through the β2-Adrenoceptor-Mediated eNOS/NO Signal Pathway

Caffeic acid phenethyl ester (CAPE), a dietary phenolic compound derived from propolis, exhibits cardiovascular and anti-inflammatory effects; however, its mechanisms in endothelial cells remain unclear. In this study, we demonstrated that CAPE induces eNOS phosphorylation and NO production in TNF-α-stimulated endothelial cells. Mechanistically, CAPE-induced NO production is mediated by Akt, PKA, and ERK signaling pathways. In silico docking and pharmacological inhibition confirmed that CAPE directly engages the β2-adrenergic receptor (β2AR) to activate the Gαs/cAMP/Epac axis. Moreover, CAPE suppresses NF-κB activation and inflammatory cytokine expression through NO-dependent mechanisms. Ex vivo studies using aortic rings further validated that CAPE stimulates eNOS activation and NO production via β2AR/Gαs signaling. Collectively, these findings indicate that CAPE enhances endothelial function and exerts anti-inflammatory effects through the β2AR-mediated signaling, highlighting its potential as a therapeutic candidate for endothelial dysfunction and inflammation-related cardiovascular diseases.