中国科学技术大学徐索文等研究人员合作发现，尿石素A可通过限制载脂蛋白E缺乏小鼠的炎症和高胆固醇血症，来促进动脉粥样硬化斑块的稳定性。2024年6月17日，国际知名学术期刊《中国药理学报》在线发表了这一成果。

研究人员表示，UroA是一种膳食植物化学物质，由肠道细菌从富含天然多酚鞣花丹宁（ET）的水果中产生。人体内ET代谢为UroA的效率取决于肠道微生物群。UroA具有多种药理活性。

Title: Urolithin A promotes atherosclerotic plaque stability by limiting inflammation and hypercholesteremia in Apolipoprotein E–deficient mice

Author: Xu, Meng-yun, Xu, Jing-jing, Kang, Li-jing, Liu, Zheng-hong, Su, Mei-ming, Zhao, Wen-qi, Wang, Zhi-hua, Sun, Lu, Xiao, Jian-bo, Evans, Paul C., Tian, Xiao-yu, Wang, Li, Huang, Yu, Liang, Xin-miao, Weng, Jian-ping, Xu, Suo-wen

Issue&Volume: 2024-06-17

Abstract: Urolithin A (UroA), a dietary phytochemical, is produced by gut bacteria from fruits rich in natural polyphenols ellagitannins (ETs). The efficiency of ETs metabolism to UroA in humans depends on gut microbiota. UroA has shown a variety of pharmacological activities. In this study we investigated the effects of UroA on atherosclerotic lesion development and stability. Apolipoprotein E-deficient (ApoE/) mice were fed a high-fat and high-cholesterol diet for 3 months to establish atherosclerosis model. Meanwhile the mice were administered UroA (50mg·kg1·d1, i.g.). We showed that UroA administration significantly decreased diet-induced atherosclerotic lesions in brachiocephalic arteries, macrophage content in plaques, expression of endothelial adhesion molecules, intraplaque hemorrhage and size of necrotic core, while increased the expression of smooth muscle actin and the thickness of fibrous cap, implying features of plaque stabilization. The underlying mechanisms were elucidated using TNF-α-stimulated human endothelial cells. Pretreatment with UroA (10, 25, 50μM) dose-dependently inhibited TNF-α-induced endothelial cell activation and monocyte adhesion. However, the anti-inflammatory effects of UroA in TNF-α-stimulated human umbilical vein endothelial cells (HUVECs) were independent of NF-κB p65 pathway. We conducted RNA-sequencing profiling analysis to identify the differential expression of genes (DEGs) associated with vascular function, inflammatory responses, cell adhesion and thrombosis in UroA-pretreated HUVECs. Human disease enrichment analysis revealed that the DEGs were significantly correlated with cardiovascular diseases. We demonstrated that UroA pretreatment mitigated endothelial inflammation by promoting NO production and decreasing YAP/TAZ protein expression and TEAD transcriptional activity in TNF-α-stimulated HUVECs. On the other hand, we found that UroA administration modulated the transcription and cleavage of lipogenic transcription factors SREBP1/2 in the liver to ameliorate cholesterol metabolism in ApoE/ mice. This study provides an experimental basis for new dietary therapeutic option to prevent atherosclerosis.

DOI: 10.1038/s41401-024-01317-5

Source: https://www.nature.com/articles/s41401-024-01317-5