Identification and functional analysis of a biflavone as a novel inhibitor of transient receptor potential vanilloid 4-dependent atherogenic processes.
Identification and functional analysis of a biflavone as a novel inhibitor of transient receptor potential vanilloid 4-dependent atherogenic processes.
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双黄酮作为瞬时受体电位香草酸4依赖性动脉粥样硬化过程抑制剂的鉴定和功能分析。
DOI：
10.1038/s41598-021-87696-9
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发表时间：
2021-04-14
影响因子：
4.6
通讯作者：
Rahaman SO
中科院分区：
文献类型：
--
作者：
Alharbi MO;Dutta B;Goswami R;Sharma S;Lei KY;Rahaman SO
动脉粥样硬化是一种大动脉慢性炎症性疾病，是心血管疾病相关死亡率和发病率日益增加的主要原因。在早期动脉粥样硬化形成过程中，由于炎症和内皮功能障碍，单核细胞迁移到主动脉内膜区域，并分化为载脂泡沫细胞，这是动脉粥样硬化的关键过程。已知许多天然化合物如类黄酮和多酚具有抗炎和抗动脉粥样硬化特性。在此，使用荧光成像板读数器支持的Ca 2+内流测定，我们报告半高通量筛选为基础的鉴定银杏黄酮，双黄酮，作为一种新的抑制剂的瞬时受体电位香草素4（TRPV 4）依赖的促动脉粥样硬化和炎症过程中的巨噬细胞。我们发现，银杏黄酮（1）阻断TRPV 4诱导的Ca 2+流入巨噬细胞，（2）通过抑制巨噬细胞对氧化低密度脂蛋白（oxLDL）的摄取而非结合来抑制oxLDL诱导的泡沫细胞形成，（3）减弱oxLDL诱导的JNK 2磷酸化、TRPV 4蛋白表达和炎症mRNA诱导。综合考虑，这项研究的结果表明，银杏黄酮抑制促动脉粥样硬化/炎症巨噬细胞功能的TRPV 4依赖的方式，从而加强了使用天然化合物开发治疗和/或化学预防分子的基本原理。
Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity. During early atherogenesis, as a result of inflammation and endothelial dysfunction, monocytes transmigrate into the aortic intimal areas, and differentiate into lipid-laden foam cells, a critical process in atherosclerosis. Numerous natural compounds such as flavonoids and polyphenols are known to have anti-inflammatory and anti-atherogenic properties. Herein, using a fluorometric imaging plate reader-supported Ca2+ influx assay, we report semi high-throughput screening-based identification of ginkgetin, a biflavone, as a novel inhibitor of transient receptor potential vanilloid 4 (TRPV4)-dependent proatherogenic and inflammatory processes in macrophages. We found that ginkgetin (1) blocks TRPV4-elicited Ca2+ influx into macrophages, (2) inhibits oxidized low-density lipoprotein (oxLDL)-induced foam cell formation by suppressing the uptake but not the binding of oxLDL in macrophages, and (3) attenuates oxLDL-induced phosphorylation of JNK2, expression of TRPV4 proteins, and induction of inflammatory mRNAs. Considered all together, the results of this study show that ginkgetin inhibits proatherogenic/inflammatory macrophage function in a TRPV4-dependent manner, thus strengthening the rationale for the use of natural compounds for developing therapeutic and/or chemopreventive molecules.
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影响因子：
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