Cannabidiol Protects the Heart From Ischemia–Reperfusion Injury Through SIRT-1/PGC-1α Activation and Nuclear Factor Kappa B Modulation: Experimental Insights

ABSTRACT: Myocardial ischemia-reperfusion (I/R) injury remains a major cause of acute cardiac dysfunction and is characterized by oxidative stress, inflammation, and apoptosis. Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has been reported to exert cardioprotective effects; however, its potential association with mitochondrial biogenesis-related signaling pathways remains incompletely understood. The aim of this study was to evaluate the cardioprotective potential of CBD in a rat myocardial I/R model and to investigate its possible association with SIRT-1/PGC-1α-related mitochondrial biogenesis and nuclear factor kappa B (NF-κB)-dependent inflammatory signaling. Forty rats were randomly assigned to 4 groups: sham, I/R, prophylactic CBD, and therapeutic CBD. Myocardial ischemia was induced by ligating the left anterior descending coronary artery for 30 minutes, followed by 30 minutes of reperfusion. Heart and aortic tissues were evaluated histopathologically, immunohistochemically, biochemically, and genetically to assess oxidative stress, inflammation, and mitochondrial biogenesis-related markers. The I/R group exhibited marked myocardial injury characterized by hyperemia, edema, hemorrhage, and inflammatory infiltration, accompanied by elevated levels of vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor, and NF-κB. By contrast, SIRT-1, PGC-1α, and B-cell lymphoma 2 (Bcl-2) expression significantly declined, alongside increased total oxidant status and oxidative stress index. Prophylactic CBD treatment notably restored myocardial architecture, suppressed inflammatory and apoptotic responses, and enhanced mitochondrial biogenesis. Therapeutic CBD administration also provided partial protection. CBD confers robust cardioprotection against myocardial I/R injury by activating the SIRT-1/PGC-1α axis, promoting mitochondrial biogenesis, and attenuating oxidative, inflammatory, and apoptotic pathways. These findings indicated that it confers significant cardioprotection against myocardial IR injury and that this protective effect is associated with modulation of SIRT-1/PGC-1α-related mitochondrial biogenesis and NF-κB-dependent inflammatory signaling. Further mechanistic studies are warranted to establish definitive causal relationships.