Activated Protein C Inhibits Lipopolysaccharide-Induced Anandamide and 2-Arachidonoylglycerol Generation In Vitro and In Vivo

Anandamide(ANA) and 2-arachidonoylglycerol(2-AG), two lipid mediators existing in the central nervous system and various peripheral tissues, have been shown to exert their diverse biological effects through cannabinoid receptors CB1 and CB2, and are therefore defined as endogenous cannabinoids. Recently, ANA and 2-AG have been shown to be generated by macrophages and platelets, respectively, by the stimulation with lipopolysaccharide(LPS) in vitro and in vivo in rats. We showed the endocannabinoids are increased in septic shock patients. Furthermore, the increased endocannabinoids are efficiently adsorbed onto polymyxin B immobilized column resulting the improvement of hypotensive shock. On the other hand it has been showed that activated protein C (APC) can ameliorate endotoxin induced-shock and -disseminated intravascular coagulation in experimental animals and patients, although the mechanisms governing its action are unknown. In the present study we found that APC inhibited the generation of ANA and 2-AG in vitro by lipopolysaccharide (LPS)-activated macrophages and platelets, respectively. Furthermore, APC significantly decreased the levels of ANA and 2-AG in the sera from rats preinfused with APC followed by LPS infusion. Consistent with the decrease of them, diminishment of hypotension and an increase in survival rate were confirmed in the APC pretreatment group. These findings demonstrate that APC can inhibit the generation of ANA and 2-AG in vitro and in vivo, and thereby suppress their induced hypotension. This action of APC may explain its efficiency in the treatment of septic shock in humans and experimental animals.