Individual and Combined Cardioprotective Effects of 1,25(OH)₂D₃ and Dimethyl Fumarate in an Isoproterenol-Induced...

Acute myocardial infarction (AMI) is closely associated with excessive oxidative stress, inflammation, and activation of the renin-angiotensin system (RAS). The active form of vitamin D [1,25(OH)₂D₃] and the Nrf2 activator dimethyl fumarate (DMF) exhibit antioxidant and anti-inflammatory effects. This study investigated the individual and combined protective roles of 1,25(OH)₂D₃ and DMF in an isoproterenol (ISO)-induced model of myocardial injury. Male Sprague-Dawley rats received ISO (85 mg/kg, two doses 24 h apart) and were pretreated with 1,25(OH)₂D₃ or DMF alone, a combination pretreatment, or a combination post-treatment. Myocardial injury was assessed using serum biomarkers, histopathology, oxidative stress markers (ROS, MDA, GSH), inflammatory markers (TNF-α), RAS components (Ang II, AT1R, ACE), and mRNA expression of Nrf2, NQO1, and NF-κB. ISO administration caused marked myocardial injury, oxidative imbalance, and increased inflammatory and RAS activation while suppressing Nrf2 and NQO1. Both 1,25(OH)₂D₃ and DMF significantly reduced oxidative stress, inflammation, and components of the RAS. Combination pretreatment and post-treatment further improved redox status and molecular markers. These groups showed elevated Nrf2 and NQO1 expression and reduced NF-κB, AT1R, and ACE expression compared with ISO controls. However, synergistic enhancement was not observed. 1,25(OH)₂D₃ and DMF provide both preventive and therapeutic protection against ISO-induced myocardial injury by modulating oxidative stress, inflammation, the Nrf2 and NF-κB signaling pathways, and RAS regulation.