TIME DEPENDENT MOLECULAR AND CELLULAR ALTERATIONS IN IRON HOMEOSTASIS AFTER ISCHEMIC INJURY OF MYOCARDIUM

Introduction: Acute myocardial infarction (MI) and subsequent cardiac dysfunction remain significant health concerns despite recent therapeutic advances. Ischemic cardiac injury triggers a wide range of cellular and molecular alterations, including dynamic changes in leukocyte subpopulations. Macrophages play a key role in all stages of MI, both in the heart and extracardiac organs, often appearing as iron-rich cells known as siderophages. While siderophages have been recognized in the lungs for decades, along with associated iron metabolism changes, their contribution to disease progression remains elusive. Thus, our objective was to characterize the dynamic changes in siderophage distribution and iron homeostasis following MI. Methods: Male Wistar rats underwent left anterior descending coronary artery ligation or sham surgery. Animals were sacrificed on day 1, 3, 7, 21 or 42 after surgery. Echocardiography was performed to assess cardiac function. Lung and cardiac tissue were collected for histology and molecular analysis. Prussian blue staining was used to detect siderophages in heart and lung sections. qRT-PCR was conducted on left ventricle (LV), right ventricle (RV), and lung samples to assess markers of inflammation, iron metabolism, and ferritinophagy. Data was analyzed with unpaired T-test or Mann-Whitney test. Results: Echocardiography, functional parameters, and increased heart weight confirmed myocardial dysfunction and heart failure development following permanent ligation. Histological analysis showed significantly greater infiltration of hemosiderin-laden macrophages in MI hearts (day 7) and lungs (day 21) compared to the sham group, and their numbers increasing over time. Inflammatory markers showed tissue- and time-dependent variations: Il6 increased at earlier time points, while Il1b increased later and only in the RV. Key genes of iron homeostasis such as Tfr1 was upregulated in both cardiac and extracardiac tissues. Hmox1 was increased in all MI samples, peaking significantly in the lung at day 21 and in the LV at day 7. Ncoa4 was elevated at day 3 in the LV and at day 42 in the RV. Cd163 was also elevated in all MI samples, reaching significance in the heart at day 21. Our results indicate a robust change in iron metabolism and suggest a potential role for ferroptosis in the adverse cardiac and extracardiac changes after MI. Conclusion: Iron metabolism dysregulation might be associated with inflammatory responses post-MI.