流行病学研究显示，大麻会增加心血管疾病（CVD）的风险；然而，对其机制所知甚少。大麻的精神活性成分Δ9-四氢大麻酚（Δ9-THC）与血管中的大麻素受体1（CB1/CNR1）结合，与心血管疾病有关。英国生物银行的一项分析发现，大麻是心血管疾病的一个危险因素。我们发现，吸食大麻会激活与心血管疾病有关的炎症细胞因子。在硅学虚拟筛选中，发现大豆异黄酮genistein是一种推定的CB1拮抗剂。人诱导的多能干细胞衍生的内皮细胞被用来模拟Δ9-THC通过NF-κB信号诱导的炎症和氧化压力。用siRNA、CRISPR干扰和genistein对CB1受体进行敲除，削弱了Δ9-THC的影响。在小鼠中，染料酶阻断了Δ9-THC诱导的线状肌内皮功能障碍，减少了动脉粥样硬化斑块，并且对中枢神经系统的渗透性最小。染料木素是一种CB1拮抗剂，可减弱Δ9-THC引起的动脉粥样硬化。
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation
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.
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