Emerging roles of protease-activated receptors in cardiometabolic disorders

Cardiometabolic disorders, including obesity-related insulin resistance and atherosclerosis, share sterile chronic inflammation as a major cause; however, the precise underlying mechanisms of chronic inflammation in cardiometabolic disorders are not fully understood. Accumulating evidence suggests that several coagulation proteases, including thrombin and activated factor X (FXa), play an important role not only in the coagulation cascade but also in the proinflammatory responses through protease-activated receptors (PARs) in many cell types. Four members of the PAR family have been cloned (PAR 1-4). For instance, thrombin activates PAR-1, PAR-3, and PAR-4. FXa activates both PAR-1 and PAR-2, while it has no effect on PAR-3 or PAR-4. Previous studies demonstrated that PAR-1 and PAR-2 activated by thrombin or FXa promote gene expression of inflammatory molecules mainly via the NF-κB and ERK1/2 pathways. In obese adipose tissue and atherosclerotic vascular tissue, various stresses increase the expression of tissue factor and procoagulant activity. Recent studies indicated that the activation of PARs in adipocytes and vascular cells by coagulation proteases promotes inflammation in these tissues, which leads to the development of cardiometabolic diseases. This review briefly summarizes the role of PARs and coagulation proteases in the pathogenesis of inflammatory diseases and describes recent findings (including ours) on the potential participation of this system in the development of cardiometabolic disorders. New insights into PARs may ensure a better understanding of cardiometabolic disorders and suggest new therapeutic options for these major health threats.