Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation

April 29, 2022 Team Members
Tzu-TangWei, Mark Chandy, Masataka Nishiga, Angela Zhang, Kaavya Krishna Kumar, Dilip Thomas, Amit Manhas, Siyeon Rhee, Johanne Marie Justesen, Ian Y. Chen, Hung-TaWo, Saereh Khanamiri, Johnson Y. Yang, Frederick J. Seidl, Noah Z. Burns, Chun Liu, Nazish Sayed, Jiun-Jie Shie, Chih-Fan Yeh, Kai-Chien Yang, Edward Lau, Kara L. Lynch, Manuel Rivas, Brian K. Kobilka, Joseph C. Wu

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 siRNACRISPR 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.

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