Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation

Tzu-Tang Wei; Mark Chandy; Masataka Nishiga; Angela Zhang; Kaavya Krishna Kumar; Dilip Thomas; Amit Manhas; Siyeon Rhee; Johanne Marie Justesen; Ian Y Chen; Hung-Ta Wo; 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

doi:10.1016/j.cell.2022.04.005

Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation

Cell. 2022 May 12;185(10):1676-1693.e23. doi: 10.1016/j.cell.2022.04.005. Epub 2022 Apr 29.

Authors

Tzu-Tang Wei¹, Mark Chandy², Masataka Nishiga³, Angela Zhang³, Kaavya Krishna Kumar⁴, Dilip Thomas³, Amit Manhas³, Siyeon Rhee², Johanne Marie Justesen⁵, Ian Y Chen³, Hung-Ta Wo⁶, Saereh Khanamiri³, Johnson Y Yang³, Frederick J Seidl⁷, Noah Z Burns⁷, Chun Liu³, Nazish Sayed³, Jiun-Jie Shie⁸, Chih-Fan Yeh⁹, Kai-Chien Yang⁹, Edward Lau¹⁰, Kara L Lynch¹¹, Manuel Rivas¹², Brian K Kobilka¹³, Joseph C Wu¹⁴

Affiliations

¹ 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.
² 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.
³ 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.
⁴ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Medicine, Division of Cardiovascular Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
⁶ 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; Division of Cardiology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
⁷ Department of Chemistry, Stanford University, Stanford, CA, USA.
⁸ Institute of Chemistry, Academia Sinica, Taipei, Taiwan.
⁹ Department and Graduate Institute of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan; Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
¹⁰ Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA.
¹¹ Department of Laboratory Medicine, University of California, San Francisco, San Francisco, CA, USA.
¹² Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁴ 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. Electronic address: joewu@stanford.edu.

Abstract

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.

Keywords: Billy Martin tetrad; G protein-coupled receptor; GPCR; UK Biobank; atherosclerosis; cardiovascular disease; human-induced pluripotent stem cell; in silico drug screening; in vivo ligand binding; marijuana.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Analgesics
Animals
Cannabinoid Receptor Agonists / pharmacology
Cannabis*
Cardiovascular Diseases*
Dronabinol / pharmacology
Endothelial Cells
Genistein / pharmacology
Genistein / therapeutic use
Hallucinogens*
Inflammation / drug therapy
Mice
Receptor, Cannabinoid, CB1
Receptors, Cannabinoid

Substances

Analgesics
Cannabinoid Receptor Agonists
Hallucinogens
Receptor, Cannabinoid, CB1
Receptors, Cannabinoid
Dronabinol
Genistein

Abstract

Publication types

MeSH terms

Substances

Grants and funding