Abstract P2117: Hypoadiponectinemia-induced Epigenetic Downregulation Of Endogenous Antioxidants Exacerbates Cardiac Ischemia-reperfusion Injury In Diabetic Mice

Diabetes worsen myocardial ischemic/reperfusion (MI/R) injury, but the underlying mechanism is still not fully understood. Epigenetics regulation is markedly involved in the process. Adiponectin (APN), a cardioprotective adipokine, is suppressed by diabetes, and dysregulated miRNAs are implicated in disease development. However, it is unclear whether hypoadiponectinemia alters cardiac miRNA profile, contributing to diabetic heart injury. Wild-type (WT) and APN knockout (APN-KO) mice were subjected to MI/R and cardiac microRNA profile were determined. Comparing those miRNAs that increased in APN-KO mice following MI/R, miR-449b was most significantly upregulated (3.98-fold over WT mice). Administering miR-449b mimic increased apoptosis, enlarged infarct size, and impaired cardiac function in WT mice. In contrast, anti-miR-449b decreased apoptosis, reduced infarct size, and improved cardiac function in APN-KO mice. In depth Bioinformatic analysis revealed oxidative stress as the top pathway regulated by miR449b. Venn analysis followed by luciferase assay identified Nrf-1 and Ucp3 as the two most important miR-449b targets. Administrating anti-miR-449b to APN-KO mice attenuated MI/R-stimulated superoxide overproduction. High glucose/high lipid in vitro treatment simulated ischemia/reperfusion upregulated miR-449b, leading to inhibition of Nrf-1 and Ucp3. These pathological effects were attenuated by anti-miR-449b or Nrf-1 overexpression. Clinically relevant cohorh study in high-fat diet (HFD)-induced diabetic mice followed with MI/R identified the copied pheonotype. Administration of anti-miR-449b or APN preserved cardiac Nrf-1 expression, reduced cardiac oxidative stress, decreased apoptosis and infarct size, and improved cardiac function. In conclusion, the study shows that hypoadiponectinemia upregulates miR-449b, suppressing Nrf-1/Ucp3 expression, which leads to oxidative stress and worsens MI/R injury. The APN/miR-449b/oxidative stress pathway could potentially be a therapeutic target for diabetic MI/R injury.