Abstract
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.
Highlights
Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity
In aortic intimal spaces, binding and uptake of oxidized low-density lipoprotein (oxLDL) by macrophages aided by scavenger receptors like SRA and CD36 creates a feedforward athero-inflammatory loop resulting in development of lipidladen foam cells, a critical process in atherosclerosis[2,3,4,5,6,7,8]
We found that overnight stimulation of macrophages with oxLDL resulted in significant upregulation of the expression of transient receptor potential vanilloid 4 (TRPV4) proteins compared to native LDL (nLDL), while expression of other receptors (CD36, TLR2, TLR4, and TLR6) remained unchanged (Figs. 4A–F)
Summary
Atherosclerosis, a chronic inflammatory disease of large arteries, is the major contributor to the growing burden of cardiovascular disease-related mortality and morbidity. 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. We reported a TRPV4-dependent exacerbation of oxLDL-induced foam cell formation in the presence of lipopolysaccharide and increasing matrix stiffness, providing a link between mechanosensing and risk of a therosclerosis[16] Considered all together, these findings suggest TRPV4 as an attractive target in atherosclerosis and other diseases, incentivizing the discovery of small molecule inhibitors of TRPV4 that can be translated into clinically effective therapeutics. We report the mechanism of action of ginkgetin against TRPV4 in the setting of macrophage foam cell formation using numerous biochemical and cellular assays
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
