Epoxide hydrolyse, a new therapeutic target for cardioprotection in insulin resistance and diabetes

We will test the hypothesis that limiting cardiac accumulation of oligomeric amylin, an amyloidogenic hormone that is elevated in the blood of patients with obesity and type-2 diabetes, delays the development of diabetic heart failure. In particular, we are trying to elucidate whether endogenous molecules with anti-aggregation effects may limit amylin oligomerization and target amylin oligomers for removal from the circulation. At the same time, we are testing methods to increase the concentration of anti-aggregation molecules in the blood, so that we can effectively reduce accumulation of oligomeric amylin in the heart. Our data show that epoxyeicosatrienoic acids, pro-fibrinolytic molecules contained in human blood and tissues, block amylin oligomerization and attachment of oligomeric amylin to the myocyte sarcolemma, and improve cardiac myocyte function. We now work with rats that express amyloidogenic human amylin and accumulate oligomeric amylin in the heart to test whether increasing the availability of epoxyeicosatrienoic acids limits cardiac amylin deposition and its deleterious effects. Our long term goal is to understand how amylin oligomers accumulate in the heart, how they affect cardiac function, and how cardiac amylin deposition could be prevented/ limited in patients with obesity and type-2 diabetes. This study will demonstrate whether endogenous pro-fibrinolytic epoxyeicosatrienoic acids are involved in removal of amylin oligomers from the circulation, thus limiting their deposition in the heart. If our hypothesis that limiting amylin oligomer deposition in the heart improves cardiac function is proven, then this study will be a basis for designing future therapeutic strategies for treating diabetic heart disease.