Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation
Journal
Cell
Journal Volume
185
Journal Issue
10
Pages
1676-1693
Date Issued
2022
Author(s)
Wei T.-T.
Chandy M.
Nishiga M.
Zhang A.
Kumar K.K.
Thomas D.
Manhas A.
Rhee S.
Justesen J.M.
Chen I.Y.
Wo H.-T.
Khanamiri S.
Yang J.Y.
Seidl F.J.
Burns N.Z.
Liu C.
Sayed N.
Shie J.-J.
Lau E.
Lynch K.L.
Rivas M.
Kobilka B.K.
Wu J.C.
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.
SDGs
Type
journal article