Investigation of the efficacy of dimethyl fumarate on cardiac regenerationthrough NRG-1/ErbB2/PI3K/Akt-1 pathway in experimental myocardial infarction (MI) induced with isoprotenol in rats

Myocardial infarction (MI) is a serious cardiovascular disease characterized by the loss of cardiomyocytes and the development of fibrosis, associated with high morbidity and mortality. Due to the limited regenerative capacity of heart tissue, current treatment methods are generally aimed at slowing the progression of the disease and managing symptoms, with a continued need for pharmacological agents that can promote tissue renewal. Dimethyl fumarate (DMF) is a compound known for its antioxidant and anti-inflammatory properties, capable of activating cellular defense mechanisms. However, the exact mechanisms by which DMF supports cardiac regeneration after MI and its effects on the NRG-1/ErbB2/PI3K/Akt-1 signaling pathway have not been fully elucidated. The primary aim of our study is to demonstrate the potential of DMF to enhance cardiac regeneration capacity and provide cardiac protection post-MI. Secondly, we aim to understand how DMF supports cardiac regeneration via the NRG-1/ErbB2/PI3K/Akt-1 signaling pathway. For this purpose, rats with experimental MI induced by isoproterenol (ISO) were divided into four groups: Control, MI, MI+Tween 80, and MI+DMF. Analyses were conducted on days 7 and 21 to study the short and long-term effects of DMF. The effects of DMF on cardiac cells post-MI were determined by measuring antioxidant capacity, inflammatory markers, and oxidative stress levels, and molecular biology techniques were used to evaluate cardiac cell proliferation and survival. The findings demonstrated that levels of NRG-1, ErbB2, and Akt-1 decreased post-MI, but DMF activated these signaling pathways to support myocardial regeneration. DMF treatment was found to reduce oxidative stress markers (TOS, OSI), increase antioxidant capacity (TAS), and suppress inflammatory responses. Histological analyses revealed increased cardiomyocyte proliferation on day 7 and reduced fibrosis formation and advanced regeneration on day 21. In conclusion, DMF was found to enhance cardiac regeneration by activating the NRG-1/ErbB2/PI3K/Akt-1 signaling pathway, suppressing oxidative stress and inflammation, thereby improving cardiomyocyte survival and function. When the data from days 7 and 21 were evaluated together, it was shown that DMF initiated the regenerative process in the early stages and supported tissue healing by reducing fibrosis in the long term. These findings indicate that DMF could be a potential therapeutic agent supporting cardiac regeneration after myocardial infarction and could contribute to the development of new treatment strategies.