A Potentially Protective Role for NRF2 in Endocannabinoid-Mediated Oxidative Stress in Human Coronary Artery Endothelial Cells.

Haas M.; Champagne K.; Gupta N.; Velarde A.; Chakour M.; Alrahal J.; Zakour G.; Augustin A.; Mooradian A. · Cell biochemistry and biophysics · 2026

**Background & Methods** This is a review article examining the role of NRF2 (nuclear factor erythroid 2-related factor 2) in endocannabinoid-mediated oxidative stress using human coronary artery endothelial cells (HCAEC). The study investigated how endocannabinoids (anandamide and 2-arachidonoyl glycerol) and Δ9-tetrahydrocannabinol affect oxidative and endoplasmic reticulum (ER) stress responses, employing molecular techniques including siRNA silencing, reporter gene assays, and pharmacological inhibitors. **Key Findings** • Endocannabinoids and tunicamycin increased superoxide generation and lipid peroxidation in HCAEC, while simultaneously triggering NRF2 mRNA expression and NRF2-dependent reporter gene activity, suggesting a compensatory antioxidant response mechanism. • Anandamide upregulated NRF2-responsive antioxidant enzyme genes including hemeoxygenase 1 (HO1), thioredoxin reductase 1 (TRX1), and NAD(P)H dehydrogenase quinone 1 (NQO1), indicating activation of protective cellular stress responses. • The PERK (PKR-like endoplasmic reticulum kinase) pathway mediated NRF2 induction by endocannabinoids, as demonstrated by siRNA silencing and the PERK inhibitor GSK2606414 preventing NRF2 activation, while ATF6 and IRE1α pathways were not involved. **Dosage & Administration** Not reported. **Safety & Adverse Effects** Not reported. **Evidence Quality** This review article presents in vitro experimental findings in a single cell model (HCAEC) with moderate mechanistic detail. Significant limitations include the lack of in vivo validation, absence of clinical human data, and restriction to a single endothelial cell type. The study does not evaluate physiologically relevant cannabinoid concentrations or assess cardiovascular outcomes. While the molecular mechanistic findings are well-controlled through use of specific inhibitors and genetic silencing, the translation to human cardiovascular disease prevention or treatment remains unclear. This represents preliminary basic science evidence (Level 5) requiring substantial additional research before clinical application can be considered. The findings are interesting but insufficient to establish therapeutic recommendations for cannabis or cannabinoid use in cardiovascular disease.

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