Studying Cardiovascular Effects of Marijuana on Healthy Individuals Using Human Derived Induced Pluripotent Stem Cells

Marijuana is the most widely used illicit drug worldwide. Epidemiological studies indicate that marijuana increases the risk of coronary artery disease (CAD). Adverse cerebrovascular and peripheral vascular effects are also associated with marijuana use. In addition, three synthetic cannabis drugs have been approved by the FDA for treating chemotherapy-induced nausea and vomiting, which also show cardiovascular side effects. Thus, both medical and recreational marijuana have adverse cardiovascular side effects. Cannabinoid CB1 receptor signaling is involved in a variety of pathophysiological processes and selective CB1 antagonists show therapeutic potential. However, the current repertoire of CB1 antagonists has psychiatric side effects and limited application. Therefore, developing new CB1 antagonists are an unmet and growing clinical need with marijuana use on the rise. Here we found compound JW-1, an isoflavone abundantly presenting in soybeans, partially docked into the CB1 receptor and inhibited CB1 activity, suggesting that compound JW-1 was a novel CB1 antagonist. Human endothelial cells were more sensitive to Δ 9 -tetrahydrocannabinol (Δ 9 -THC) than cardiomyocytes and cardiac fibroblasts. To determine the mechanism of Δ 9 -THC pathological effects on the vasculature, we generated human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) from 5 healthy individuals. CB1 receptor was expressed in all hiPSC-ECs, whilst CB2 expression was low. Δ 9 -THC induced inflammation and oxidative stress via NF-κB signaling activated in hiPSC-ECs. Knockdown of CB1 receptor with siRNA, abrogation of receptor expression with CRISPRi and compound JW-1 treatment could rescue the effect of Δ 9 -THC. Furthermore, compound JW-1 blocked Δ 9 -THC-induced endothelial dysfunction in mice models. Our investigations reveal that Δ 9 -THC causes endothelial dysfunction via the CB1 receptor. Compound JW-1 is a novel CB1 antagonist that can be used for preventing Δ 9 -THC-induced side effects.