Shinjulactone A Blocks Vascular Inflammation and the Endothelial-Mesenchymal Transition
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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 lipopolysaccharide-induced 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.
Abstract
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 lipopolysaccharide-induced 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.
참고문헌 (19)
- Wu MY, "New insights into the role of inflammation in the pathogenesis of atherosclerosis", Int J Mol Sci, 18, pp.2034~ (2017)
- Hu W, "Puerarin inhibits adhesion molecule expression in tnf-α-stimulated human endothelial cells via modulation of the nuclear factor kappaB pathway", Pharmacology, 85, pp.27~35 (2010)
- Gareus R, "Endothelial cell-specific NF-kappaB inhibition protects mice from atherosclerosis", Cell Metab, 8, pp.372~383 (2008)
- Kirii H, "Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice", Arterioscler Thromb Vasc Biol, 23, pp.656~660 (2003)
- Libby P, "Interleukin-1 beta as a target for atherosclerosis therapy : biological basis of CANTOS and beyond", J Am Coll Cardiol, 70, pp.2278~2289 (2017)
- Gualtieri P, "Psychobiotics regulate the anxiety symptoms in carriers of allele A of IL-1β gene : a randomized, placebo-controlled clinical trial", Mediators Inflamm, 2020, pp.2346126~ (2020)
- Souilhol C, "Endothelial-mesenchymal transition in atherosclerosis", Cardiovasc Res, 114, pp.565~577 (2018)
- Jackson AO, "Endothelial-to-mesenchymal transition : A novel therapeutic target for cardiovascular diseases", Trends Cardiovasc Med, 27, pp.383~393 (2017)
- Rieder F, "Inflammation-induced endothelial-to-mesenchymal transition : a novel mechanism of intestinal fibrosis", Am J Pathol, 179, pp.2660~2673 (2011)
- Ley K, "Getting to the site of inflammation : the leukocyte adhesion cascade updated", Nat Rev Immunol, 7, pp.678~689 (2007)
- Deshpande R, "Estradiol down-regulates LPS-induced cytokine production and NFkB activation in murine macrophages", Am J Reprod Immunol, 38, pp.46~54 (1997)
- De Martino L, "Chemistry and biological activities of Ailanthus altissima Swingle : a review", Pharmacogn Rev, 2, pp.339~350 (2008)
- Fiaschetti G, "Quassinoids : From traditional drugs to new cancer therapeutics", Curr Med Chem, 18, pp.316~328 (2011)
- van Diepen JA, "Interactions between inflammation and lipid metabolism : relevance for efficacy of anti-inflammatory drugs in the treatment of atherosclerosis", Atherosclerosis, 228, pp.306~315 (2013)
- Sima AV, "Vascular endothelium in atherosclerosis", Cell Tissue Res, 335, pp.191~203 (2009)
- Yu XH, "Nuclear factor-κB activation as a pathological mechanism of lipid metabolism and atherosclerosis", Adv Clin Chem, 70, pp.1~30 (2015)
- Lawrence T, "The resolution of inflammation : anti-inflammatory roles for NF-kappaB", Int J Biochem Cell Biol, 42, pp.519~523 (2010)
- Sánchez-Duffhues G, "Endothelial-to-mesenchymal transition in cardiovascular diseases : developmental signaling pathways gone awry", Dev Dyn, 247, pp.492~508 (2018)
- Libby P, "Inflammatory mechanisms : the molecular basis of inflammation and disease", Nutr Rev, 65, pp.S140~S146 (2007)