Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation
Cell, 2022
Wei T., Chandy M., Nishiga M., Zhang A., Kumar K., Thomas D., Manhas A., Rhee S., Justesen J., Chen I., Wo H., Khanamiri S., Yang J., Seidl F., Burns N., Liu C., Sayed N., Shie J., Yeh C., Yang K., Lau E., Lynch K., Rivas M., Kobilka B., Wu J.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma | O Olink Target 96 |
Abstract
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ9-tetrahydrocannabinol (Δ9-THC), the psychoactive component of marijuana, binds to cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis was an risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells were used to model Δ9-THC-induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of Δ9-THC. In mice, genistein blocked Δ9-THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system. Genistein is a CB1 antagonist that attenuates Δ9-THC-induced atherosclerosis.