Abstract 8105: The Nucleotide-Binding Oligomerization Domain-Containing Protein 1 Underlies Cardiac Apoptosis in Type 2 Diabetic Mice

Abstract

Introduction. The pathogenesis of diabetic cardiomyopathy is complex, and involves deregulated lipid metabolism, insulin resistance, mitochondrial dysfunction together with a chronic inflammatory state and cardiac apoptosis sensitization. It has been proposed that the innate immune response contributes to the onset of diabetes. Indeed, both Toll-like (TLRs) and Nucleotide-binding oligomerization domain-like (NLRs) receptors have been implicated in the pathogenesis of insulin resistance and diabetes. However, less is known regarding the contribution of these receptors to diabetic cardiac disease. Although increased cardiomyocyte (Cm) apoptosis has been described in the heart of diabetic (db) mice, the mechanisms for increased cell death remain unknown. NLR proteins have functions beyond those in the innate immune response, including the regulation of the apoptotic process. In this regard, a relationship between a subfamily of NLR, nucleotide-binding oligomerization domain-containing protein-1 (NOD1) and the caspase activation has been established. In this report we analyze the involvement of NOD1 in cardiac apoptosis related to type 2 diabetes. Methods and Results. We used a genetic mouse model of type 2 diabetes that mimics several symptoms found in type 2 diabetic patients, including obesity, hyperglycemia, hyperinsulinemia and depressed cardiac function. Our results demonstrate the expression of NOD1 in cardiac tissue, providing the first evidence of an up-regulation of NOD1-pathway in hearts of db mice. We also detect the activation of RIP2, a kinase involved in NOD1 signaling. Concomitant to these observations, chronic activation of NF-κB and apoptotic-pathways (caspase 3 and Bax over-expression and X-IAP down-regulation) were observed in hearts of db mice. At the cellular level, native Cms showed higher protein levels of NOD1 compared to wild type. As a proof of concept, both selective activation (iEDAP) and down-regulation of NOD1 (siRNA) modulate NF-κB and apoptotic-pathways in cardiac cells. In conclusion , our results indicate that cardiac NOD1 induction may participate in the process of Cms apoptosis related to diabetic cardiomyopathy and open a new paradigm linking NLRs to the cardiac damage related to type 2 diabetes.