AGE and RAGE Precursor Pathway Driven Mechanisms of Ischemia Reperfusion Injury in Diabetic Heart

Innate dysfunction in the vascular arterial structures and myocardium, in part, primes diabetic subjects for increased vulnerability to superimposed stresses, including ischemia/reperfusion (I/R) injury. Morbidity and mortality due to myocardial infarction are higher in patients with diabetes. The biochemical changes that occur within cardiomyocytes subjected to ischemia are exacerbated by reperfusion; however, the precise mechanisms mediating myocardial I/R injury have not been fully elucidated. We have focused on dysregulated glucose metabolism, defined as glucose metabolism by pathways such as polyol pathway that does not lead to energy production, rather cofactor consumption, as a key mechanism leading to cardiac dysfunction in diabetes, as well as enhancing vulnerability to myocardial I/R injury. Our studies demonstrate that increases in glucose/substrate flux via polyol pathway enzyme aldose reductase (AR) lead to increases in generation of advanced glycation end product (AGE) precursors 3–deoxyglucosone (3-DG) and methylglyoxal (MG), and AGEs, leading to increases in interactions of these AGEs with the receptor for advanced glycation end-products (RAGE). RAGE regulates the cellular response to cardiac tissue damage in I/R, an effect potentially mediated by the RAGE cytoplasmic domain binding to the diaphanous-related formin DIAPH1. Emerging data from our recent studies indicate that genetic deletion of Diaph1 reduces infarct size and improves contractile function after I/R. Silencing Diaph1 downregulated actin polymerization and serum response factor-regulated gene expression. Importantly, these changes led to increased sarcoplasmic reticulum Ca²⁺ ATPase expression, and reduced sodium calcium exchanger expression. Taken together, our studies demonstrate that polyol pathway is integrally linked to AGE-RAGE driven mechanisms of I/R injury and that RAGE actions require DIAPH1. Our work suggests that targeting RAGE-DIAPH1 may represent a novel avenue for myocardial salvage after acute infarction in patients with diabetes.