大麻素受体 1 拮抗剂染料木黄酮可减轻大麻引起的血管炎症。
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.
机构信息
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA; Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Chemical Biology and Molecular Biophysics, Taiwan International Graduate Program in Chemical Biology and Molecular Biophysics (TIGP-CBMB), Academia Sinica, Taipei, Taiwan.
Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Radiology, Molecular Imaging Program at Stanford, Stanford University, Stanford, CA 94305, USA; Greenstone Biosciences, Palo Alto, CA 94304, USA.
出版信息
Cell. 2022 May 12;185(10):1676-1693.e23. doi: 10.1016/j.cell.2022.04.005. Epub 2022 Apr 29.
Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ-tetrahydrocannabinol (Δ-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 Δ-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 Δ-THC. In mice, genistein blocked Δ-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 Δ-THC-induced atherosclerosis.
流行病学研究表明，大麻会增加心血管疾病（CVD）的风险；然而，其具体机制尚不清楚。大麻中的精神活性成分Δ-四氢大麻酚（Δ-THC）与血管中的大麻素受体 1（CB1/CNR1）结合，并与 CVD 有关。英国生物银行的一项分析发现，大麻是 CVD 的一个风险因素。我们发现大麻吸烟会激活与 CVD 相关的炎症细胞因子。计算机虚拟筛选确定染料木黄酮，一种大豆异黄酮，是一种潜在的 CB1 拮抗剂。人类诱导多能干细胞衍生的内皮细胞通过 NF-κB 信号通路被用于模拟 Δ-THC 诱导的炎症和氧化应激。用 siRNA、CRISPR 干扰和染料木黄酮敲低 CB1 受体可减弱 Δ-THC 的作用。在小鼠中，染料木黄酮可阻止线描肌动图中 Δ-THC 引起的内皮功能障碍，减少动脉粥样硬化斑块，且对中枢神经系统的穿透性极小。染料木黄酮是一种可减弱 Δ-THC 诱导的动脉粥样硬化的 CB1 拮抗剂。
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