Exogenous Thyroxine Increases Cardiac Nrf2-TRX Associated with a Reduction in Oxidative Injury and Inflammation in Insulin Resistant OLETF Rats

Cardiovascular disease (CVD) is the leading cause of death among individuals with Type II diabetes (T2D), affecting approximately 30 million people in the United States. During insulin resistance, the heart undergoes a metabolic shift, leading to increased reactive oxygen species (ROS) generation, lipotoxicity, and mitochondrial dysfunction, ultimately contributing to cardiovascular dysfunction. The effects of thyroid hormones (THs) on redox biology and oxidative stress remain inconclusive, necessitating further investigation. In this study, insulin-resistant Otsuka Long Evans Tokushima Fatty (OLETF) rats were used to assess the impact of exogenous thyroxine (exoT4) on NADPH oxidases (NOX) and antioxidant defenses in the heart. Rats were assigned to four groups: (1) lean control, Long Evans Tokushima Otsuka (LETO; n=6), (2) LETO + T4 (8 μg/100g BM/day for 5 weeks; n=7), (3) untreated OLETF (n=6), and (4) OLETF + T4 (n=7). NOX4 mRNA expression was two-fold greater in OLETF rats compared to LETO. T4 treatment increased NOX4 protein abundance by 56% in OLETF. Additionally, T4 normalized lipid peroxidation (4-hydroxynonenal) and tumor necrosis factor-α (TNF-α) levels while increasing nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA expression by 158% compared to LETO and enhancing nuclear Nrf2 protein expression by 45% compared to untreated OLETF. Thioredoxin (TRX) expression, suppressed in OLETF, was increased by 88% following T4 treatment. ExoT4 increased mitofusin 2 (Mfn2) protein abundance in OLETF by 49% compared to LETO. These findings suggest that thyroid hormone treatment may have cardioprotective effects mediated by Nrf2 in the heart during metabolic syndrome (MetS).