Exogenous Thyroxine Increases Cardiac Nrf2 and the Potential to Upregulate Nrf2-Mediated Antioxidant Defense Mechanisms in Insulin Resistant OLETF rats

Cardiovascular disease (CVD) is the leading cause of death among individuals with Type II diabetes (T2D) with approximately 30 million people afflicted within the United States. Diabetic cardiomyopathy is defined as cardiovascular dysfunction induced by diabetic complications such as sustained hyperglycemia and insulin resistance. During insulin resistance the heart undergoes a metabolic shift in which fatty acids (FA) accounts for about 99% of the ATP production. Some major consequences of a metabolic shift with impaired glucose tolerance can cause an increase in reactive oxygen species (ROS), lipotoxicity, mitochondrial dysfunction, ultimately leading to cardiovascular dysfunction. We have previously shown thyroid hormones (THs) increase GLUT4 translocation in cardiac tissue, indicating the potential to improve the impaired glucose metabolism in the heart. THs have also been shown to improve oxidative injury and increase antioxidant defense systems yet contradicting data exists demonstrating THs induce oxidative stress. Thus, the effects of THs on redox biology and oxidative stress are incongruent and warrant further investigation. Insulin resistant, Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the effects of exogenous thyroxine (T4) on oxidative damage and antioxidant defense in cardiac tissue. Rats were assigned to four groups: 1) lean, Long Evans Tokushima Otsuka (LETO; n=6), 2) LETO + T4 (8 μg/100g BM/d × 5 wks; n=7), 3) untreated OLETF (n=6), and 4) OLETF + T4 (n=7). T4 increased NADPH oxidase (NOX) NOX2 mRNA in both treated LETO (2.04 ± 0.6) and OLETF (2.02 ± 0.6) compared to LETO control (1 ± 0.2). T4 further increased NOX4 mRNA in OLETF by 78% compared to untreated OLETF. In addition, T4 increased Nuclear factor-erythroid factor 2-related factor 2 (Nrf2) protein expression in OLETF by 45% compared to untreated OLETF. These data suggest that the potential for an oxidizing environment in the insulin resistant OLETF rat is increased and T4 has the cardioprotective potential to increase Nrf2-mediated antioxidant defense mechanisms. APS Porter Fellowship and American Heart Association grant # 946746. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.