Insulin Regulated Aminopeptidase (IRAP) Inhibition – A Novel Treatment for Diabetes-Induced Cardiovascular Disease

Background
Cardiovascular diseases (CVDs) are the leading cause of death in patients with diabetes mellitus (DM), with no targeted therapies currently available. We have identified the enzyme insulin regulated aminopeptidase (IRAP) as a potential target in treatment of CVD, however, the effect of IRAP inhibition on diabetes-induced CVD are unknown. The current study investigated the effect of intervention with chronic IRAP inhibitor (IRAPi) treatment on cardiac pathology in both an STZ-induced mouse model of type 1 diabetes (T1D) and a high fat, high sucrose (HFHS)-induced type 2 (T2D) diabetic rat model.

Methods/Results
Chronic IRAPi treatment had no direct effect to reduce basal blood glucose levels or alter glucose handling in either diabetic model. Both models of diabetes resulted in increased cardiac IRAP expression. STZ-induced diabetes significantly increased cardiac fibrosis when compared with citrate controls, with IRAPi treatment attenuating the STZ-induced increase in fibrosis. These effects were associated with reversal of diabetes-induced increases in cardiac myofibroblast and superoxide expression, as well as reduced expression of the inflammatory markers phospho-IκBα, MCP1 and F480. In agreement, diabetic IRAP KO mice were protected from developing these pathologies. Similar effects were demonstrated in the T2D rat model, in addition to improvement in diastolic function following 8 weeks of IRAPi treatment when compared to vehicle treated diabetic rats.

Conclusions
Our study demonstrates for the first time that IRAP inhibition displays striking cardioprotective effects in two preclinical models of diabetes-induced CVD, validating pharmacological IRAP inhibition as a novel therapeutic strategy to treat this complex problem.