Involvement of SIRT3/FOXO1 and TLR4/NF-κB/NLRP3 pathways in protective effects of Δ(9)-tetrahydrocannabinol on diabetic cardiomyopathy in rats

Abstract Objectives Diabetic cardiomyopathy (DCM) is a chronic complication of type 2 diabetes mellitus, leading to heart failure. Addressing DCM requires a comprehensive therapeutic approach. This study examines the protective role of Δ(9)-tetrahydrocannabinol (THC) in DCM by assessing its impact on cardiac function, inflammation, oxidative stress, and mitochondrial health and exploring the involvement of the SIRT3/FOXO1 and TLR4/NF-κB/NLRP3 signaling pathways. Methods Over a four-week period, THC (1.5 mg/kg, administered intraperitoneally) was given to type-2 diabetic Sprague-Dawley rats. Cardiac function was evaluated using a carotid catheter in vivo while mitochondrial integrity was assessed through fluorometric techniques. Moreover, cardiac biochemical biomarkers and the protein expression of key signaling proteins were measured via ELISA and immunoblotting. Results Compared to untreated diabetic rats, THC treatment showed pronounced protective effects, improving cardiac function and reducing markers of DCM. It significantly lowered the expression of NF-κB, NLRP3, IL-1β, and TNF-α while reducing diabetes-induced oxidative stress in the heart, as evidenced by decreased malondialdehyde levels and increased glutathione and catalase levels. THC also prevented mitochondrial membrane depolarization and reactive oxygen species production and substantially suppressed the upregulation of TLR4 and MyD88 while increasing FOXO1 expression in diabetic rats. Inhibition of the SIRT3/FOXO1 pathway using 3-TYP reversed the cardioprotective effects of THC, negating its impact on mitochondrial function and the expression of NF-κB/NLRP3/IL-1β without influencing TLR4/MyD88. Conclusions These results underscore that THC offers significant protection against diabetes-induced cardiac damage by mitigating functional and biochemical changes associated with DCM, primarily through modulation of the TLR4/NF-κB/NLRP3 and SIRT3/FOXO1/mitochondrial pathways.