| Cells of the innate immune system play a major role in the pathology of both cardiovascular disease and obesity-associated insulin resistance. They are the first line of host defense, becoming activated by foreign pathogens, hyperlipidemia, oxidized low density lipoprotein, hyperglycemia, or advanced glycation products. Activation of innate immunity leads to increased cytokine and chemokine production, immune cell proliferation, and recruitment of monocytes to atherosclerotic lesions and obese white adipose tissue. Much remains to be defined as to the roles of individual receptors and their effects on disease.;The aim of these studies was to examine whether antagonism of select cell surface receptors, P-selectin and CX3CR1, involved in leukocyte trafficking, would ameliorate dysfunction in rodent models of cardiovascular disease and obesity-associated insulin resistance.;Surface plasmon resonance (Biacore) was used to identify small molecule inhibitors of P-selectin. P-selectin inhibitors were further characterized in cell- based binding assays and in rodent models of leukocyte rolling, restenosis, and venous stasis. Our studies identified a small molecule inhibitor, PSI-697, that inhibited binding of P-selectin to recombinant P-selectin glycoprotein ligand-1 in both the Biacore and a cell-based binding assays. PSI-697 inhibited leukocyte rolling in a rat intravital microscopy model, reduced restenosis in a balloon arterial injury model, and reduced thrombus formation in a rat venous stasis model. The action of PSI-697 in these models is consistent with it being an antagonist of P-selectin and is effective in reducing measures of disease.;Genetically modified mice in which the CX3CR1 gene was globally deleted were used in a diet induced obesity model to determine if deletion of CX3CR1 is sufficient to reduce obesity-induced insulin resistance and macrophage accumulation in adipose tissue. Mice were placed on five diets, low and high fat lard diets, and low fat, high fat and high fat plus sucrose oil diets. Deletion of CX3CR1 had modest effects on glucose homeostasis, increased serum adiponectin and reduced serum monocyte chemoattractant-1 in oil diets, but had no effect in lard diets. Macrophage accumulation and inflammatory gene and protein expression were more affected by diet fat source than CX3CR1 deletion. Genetic deletion of CX3CR1 is insufficient to ameliorate obesity-induced insulin resistance. |
