Individual and Combined Cardioprotective Effects of 1,25(OH) 2 D 3 and Dimethyl Fumarate in an Isoproterenol‐Induced Myocardial Injury Model
Fatma Hande Karpuzoğlu, Serhat Kilinç, İlayda Sözmen, İlknur Bingül, Abdurrahman Fatih Aydin, Aysel Bayram, Semen Önder, Efe Akçe, Semra Doğru‐Abbasoğlu, Müjdat UysalABSTRACT
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) 2 D 3 ] 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) 2 D 3 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) 2 D 3 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) 2 D 3 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) 2 D 3 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.