(733.23) Emerging Role of Nrf2 in Altering Cardiac Iron Metabolism during Myocardial Infarction

Poster Board Number: E290

Deepthy Jayakumar (University of Madras), Kishore Kumar S Narasimhan (Creighton University), Abinayaa Rajkumar (University of Madras), Malathi Raghunathan (University of Madras), Sandhya Sundaram (Sri Ramachandra Institute of Higher Education and Research), Kalaiselvi Periandavan (University of Madras, University of Madras)

Cardiac function demands a combination of iron availability for its high energy requirement and tight regulation of redox signaling. Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a master transcriptional regulator of antioxidant/cytoprotective genes and recent reports has emphasized its role in regulating iron metabolism and ferroptosis in various pathologies including cardiovascular diseases. We hypothesized that iron metabolism is deregulated in myocardial infarction (MI) through alterations in Nrf2/hepcidin/ferroportin axis. Adult Wistar rats weighing ~200g were administered with isoproterenol (ISO; 85mg/kg body weight) subcutaneously for two days to induce MI. After the experimental period, the heart and blood were collected under ketamine/xylazine anesthesia. Morphological, histopathological, serum markers (cTnT, CK amp; LDH), inflammatory cytokines and western blotting analyses for Nrf2 and key proteins involved in iron trafficking and metabolism were performed. Morphological examination (left ventricle/tibia length; LV/TL) revealed maladaptive remodeling in ISO-administered rats (P=0.0002). Histopathological analysis demonstrated normal cardiac architecture with a proper myofibrillar arrangement in vehicle-administered rats, whereas in ISO-administered rats disoriented myofibril with intense neutrophil infiltration and necrotic impressions were observed. Further, a marked elevation (Plt;0.05) in the inflammatory markers IL6, TNFα, IL1α, and CRP were observed in ISO-administered rats which corroborates with the neutrophil infiltration/necrotic impressions in these animals. We also observed elevated cTnT, CK and LDH (Plt;0.05) whereas the total iron was decreased (P=0.0286) in the serum of ISO-administered rats. In contrast, we detected that labile redox-active iron was increased in the heart of ISO-administered rats. Western blot analysis in the heart tissues from vehicle and ISO-administered (remote, peri-infarct and infarct zones) rats revealed an augmentation in HIF1α, hepcidin, and ferritin (Plt;0.05) levels whereas no significant changes were seen in ferroportin. This increment in hepcidin/ferroportin ratio substantiates the augmented levels of iron within the cardiac tissue. Subsequently, we found elevated accumulation of Nrf2 in the nucleus of ISO-administered rats highlighting its transcriptional activity which was demonstrated further by increase in the levels of its downstream targets NQO1 and HMOX-1. Overall, augmented Nrf2-transcriptional activity during MI regulates iron metabolism through hepcidin/ferroportin axis which in turn leads to iron sequestration within the cardiomyocytes and exacerbates MI.

The financial assistance to Ms. Deepthy Jayakumar, Department of Medical lt;a href="https://www.sciencedirect.com/topics/earth-and-planetary-sciences/biochemistry" title="Learn more about Biochemistry from ScienceDirects AI-generated Topic Pages"gt;Biochemistrylt;/agt;, Dr ALM PGIBMS, University of Madras from University Grants Commission and Council of Scientific amp;amp; Industrial Research (UGC-CSIR), New Delhi, Government of India in the form of Junior Research Fellow (JRF) is gratefully acknowledged.