Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.
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DOI：
10.1016/j.cell.2022.04.005
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发表时间：
2022-05-12
期刊：
影响因子：
64.5
通讯作者：
Wu, Joseph C.
中科院分区：
文献类型：
--
作者：
Wei, Tzu-Tang;Chandy, Mark;Nishiga, Masataka;Zhang, Angela;Kumar, Kaavya Krishna;Thomas, Dilip;Manhas, Amit;Rhee, Siyeon;Justesen, Johanne Marie;Chen, Ian Y.;Wo, Hung-Ta;Khanamiri, Saereh;Yang, Johnson Y.;Seidl, Frederick J.;Burns, Noah Z.;Liu, Chun;Sayed, Nazish;Shie, Jiun-Jie;Yeh, Chih-Fan;Yang, Kai-Chien;Lau, Edward;Lynch, Kara L.;Rivas, Manuel;Kobilka, Brian K.;Wu, Joseph C.
流行病学研究表明，大麻会增加心血管疾病（CVD）的风险;然而，人们对其机制知之甚少。Δ9-四氢大麻酚（Δ9-THC）是大麻的精神活性成分，与血管系统中的大麻素受体1（CB 1/CNR 1）结合，并与CVD有关。英国生物银行的一项分析发现，大麻是CVD的一个危险因素。我们发现吸食大麻激活了与CVD有关的炎症细胞因子。在计算机虚拟筛选确定染料木素，大豆异黄酮，作为一个假定的CB 1拮抗剂。使用人诱导的多能干细胞衍生的内皮细胞通过NF-κB信号传导模拟Δ9-THC诱导的炎症和氧化应激。用siRNA、CRISPR干扰和染料木黄酮敲低CB 1受体减弱了Δ9-THC的作用。在小鼠中，染料木黄酮阻断了钢丝肌描记器中Δ9-THC诱导的内皮功能障碍，减少了动脉粥样硬化斑块，并且对中枢神经系统的渗透最小。Genistein是一种CB 1拮抗剂，可减弱Δ9-THC诱导的动脉粥样硬化。避孕药的使用呈上升趋势，并与心血管疾病有关。Δ9-四氢大麻酚（Δ9-THC）是大麻的迷幻成分，通过大麻素受体1引起血管炎症，氧化应激和动脉粥样硬化。染料木黄酮是一种大豆异黄酮，可阻断Δ9-THC的有害心血管作用，同时保留临床有用的作用，如镇静和镇痛。
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. Marijuana use is on the rise and is associated with cardiovascular disease. Δ9-tetrahydrocannabinol (Δ9-THC), the psychedelic component of marijuana, causes vascular inflammation, oxidative stress, and atherosclerosis via cannabinoid receptor 1. Genistein, a soybean isoflavone, blocks harmful cardiovascular effects of Δ9-THC while preserving clinically useful effects such as sedation and analgesia.
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