Objective: Vascular inflammation contributes to the development of many chronic human diseases. Inflammatory stimuli such as interleukin (IL)-1β or disturbed blood flow trigger endothelial activation, thereby promoting leukocyte recruitment and transmigration through inflammatory signaling pathways. This study aimed to identify novel compounds capable of blocking vascular inflammation, with potential therapeutic applications in vascular inflammatory diseases such as atherosclerosis. Methods: A natural compound library was screened to identify drug candidates that inhibit IL-1β-induced endothelial inflammation. The anti-inflammatory effects of tigloylgomisin P, one of the hit compounds, were examined in bovine aortic endothelial cells stimulated with IL-1β or oscillatory (disturbed) flow. Endothelial inflammation was assessed by measuring nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) phosphorylation and nuclear translocation, monocyte adhesion to endothelial monolayers, and Smad1/5/9 phosphorylation in vitro. Vascular inflammation in vivo was evaluated in aortas of apolipoprotein E (ApoE) knockout mice treated with tigloylgomisin P using immunohistochemistry. Results: Tigloylgomisin P suppressed IL-1β-induced NF-κB activation and reduced monocyte adhesion. In addition, it inhibited oscillatory shear stress-induced endothelial inflammation mediated by NF-κB activation and Smad1/5/9 phosphorylation. In ApoE knockout mice, administration of tigloylgomisin P decreased inflammatory marker expression in the atheroprone inner curvature of aortic arches. Conclusion These findings suggest that tigloylgomisin P may represent a potential therapeutic agent for vascular inflammatory diseases such as atherosclerosis.

Objective: The endothelial inflammatory response plays an important role in atherogenesis by inducing nuclear factor (NF)κB-dependent cell adhesion molecule expression and monocyte recruitment. Here, we screened for natural ligands and investigated the ability of shinjulactone A to inhibit interleukin-1β (IL-1β)-induced endothelial inflammatory signaling. Methods: The natural compound library included 880 single compounds isolated from medicinal plants by the Korean Medicinal Material Bank. Primary endothelial cells were pretreated with single compounds before stimulation with IL-1β to induce endothelial inflammation. Endothelial inflammation was measured by assaying NFκB activation and monocyte adhesion. The endothelial-mesenchymal transition (EndMT) was evaluated using cell type-specific marker protein expression and morphology. Results: Shinjulactone A was identified as an efficient blocker of IL-1β -induced NFκB activation, with a half-maximal inhibitory concentration of approximately 1 µM, and monocyte recruitment in endothelial cells. However, it did not affect lipopolysaccharideinduced NFκB activation in macrophages. Compared to Bay 11-782, a well-known NFκB inhibitor that shows considerable cytotoxicity during long-term treatment, shinjulactone A did not affect endothelial cell viability. Furthermore, it also significantly inhibited the EndMT, which is known to promote atherosclerosis and plaque instability. Conclusion We suggest that shinjulactone A may be an effective and safe drug candidate for atherosclerosis because it targets and inhibits both endothelial inflammation and the EndMT, without impairing NFκB-dependent innate immunity in macrophages.