The role of TLR-mediated inflammation in diabetic cardiomyopathy
Jean Schaffer   (Saint Louis, MO)
Cardiovascular disease is the leading cause of death in diabetics who suffer from aggressive atherosclerosis and cardiomyopathy. Inflammation is now recognized as a central feature of obesity, insulin resistance, and diabetes. Nonetheless, the role of inflammatory pathways in the pathogenesis of diabetic cardiac dysfunction has been largely unexplored. Evidence is emerging that Toll-like receptor (TLR) 4 and 2, originally identified as host receptors for bacterial lipids and lipoproteins such as lipopolysaccharide (LPS), contribute to systemic insulin resistance in lipid overload states through a mechanism that may involve activation by saturated fatty acids. Our preliminary studies demonstrate alterations in myocardial lipid metabolism can activate inflammatory signaling in vivo. We will use mouse models of lipotoxic cardiomyopathy and diabetic cardiomyopathy combined with TLR4 and TLR2 loss of function to test the hypothesis that TLR-mediated inflammatory signaling contributes to the pathogenesis of diabetic cardiac dysfunction.