Therapeutic Interventions of Endocannabinoid Signaling in Obesity-Related Cardiovascular Dysfunction

Obesity is a major risk factor involved in the progression of cardiovascular diseases. The aggravation of cardiovascular diseases is primarily linked to the release of pro-inflammatory cytokines. The endocannabinoid system (ECS) plays an important role in various diseases such as obesity, inflammation, Type II diabetes mellitus (T2DM) and cardiovascular dysfunction (CVD). ECS comprises of endocannabinoid receptors; cannabinoid 1 (CB1), cannabinoid 2 (CB2) and cannabinoid enzymes which are responsible for regulation of signaling pathways involved in obesity and CVD. The potential therapeutic interventions by drugs acting on cannabinoid receptors and their usage in the mitigation of obesity and CVD has been demonstrated in various pre-clinical and clinical studies. The expression of CB1 inhibition and CB2 activation receptors has been observed in the CVDs and obesity. Several reports suggest that; inhibition of centrally acting CB1 receptor antagonist show a significant reduction of obesity, atherosclerosis and modulate blood pressure. These therapeutic agents have also been reported to be associated with unwanted side effects. Rimonabant (SR141716/Acomplia/Zimulti), a selective CB1 inverse agonist had shown promising anti-obesity and anti-CVD effects, but later was withdrawn due to severe neuropsychiatric side-effects. The researchers are now exploring alternative approaches to block CB1 receptors by avoiding psychotropic effects. Drugs like TXX-522 have been developed to exhibit good binding capacity to CB1 receptors and have lesser brain penetration. Numerous studies have reported that, CB2 receptor agonists prevent the onset of cardio metabolic diseases by scavenging free radicals and attenuating inflammation. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes inhibition lead to reduction in the reactive oxygen species and regulation of apoptotic pathway, thus ameliorating the elevated biomarkers responsible for obesity and CVD. The central idea of this review is to examine the mechanism of action of cannabinoid receptors and to explore the therapeutic interventions at cellular and molecular levels with respect to their anti-obesity and cardiovascular effects.