Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. ?9-tetrahydrocannabinol (?9-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 ?9-THC-induced inflammation and oxidative stress via NF-?B signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference, and genistein attenuated the effects of ?9-THC. In mice, genistein blocked ?9-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 ?9-THC-induced atherosclerosis.
View details for DOI 10.1016/j.cell.2022.04.005
View details for PubMedID 35489334