Ironing out the role of Nrf2 in cardiac iron metabolism during myocardial infarction
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Background and Purpose
Iron plays a crucial role in maintaining cardiac health. However, existing research has focused on understanding how cardiac cells regulates intercellular iron levels through their own cell-autonomous cardiac hepcidin/ferroportin axis. In Addition, several studies have explored the mechanisms linking cardiac dysfunction with iron imbalance. Recent insights also emphasize the importance of Nrf2, a key transcriptional regulator that not only counteracts iron-mediated oxidative stress, but also governs several genes involved in iron metabolism. Consequently, the Nrf2/hepcidin/ferroportin axis is emerging as a central hub connecting cardiac iron metabolism with redox alterations. However, the precise mechanisms linking these components remain elusive. This study aims to elucidate how disruptions in the Nrf2/hepcidin/ferroportin axis contribute to the altered iron metabolism in Myocardial infarction (MI).
Experimental Approach
MI was induced in adult Wistar rats by subcutaneous administration of isoproterenol (ISO; 85 mg/kg body weight) for two days. H9c2 cardiomyoblasts were differentiated into cardiomyocytes using all-trans-retinoic acid (ATRA, 2.5μM for 5-days) and subjected to hypoxic stress using CoCl 2 (100μM). In vitro pharmacological suppression of Nrf2 was performed using brusatol (50nM).
Key Results
Morphological examination revealed maladaptive remodeling, and histopathological analysis demonstrated disoriented myofibrils with intense neutrophil infiltration and necrotic impressions in MI-affected animals. Furthermore, elevated levels of labile redox-active iron and inflammatory markers were observed in serum of ISO induced animals. qPCR & Western blot analysis indicated an increase in HIF-1α and hepcidin levels, and downregulation of FTH levels in MI-induced animals, with no significant changes observed in FPN-1. The transcriptional activity of Nrf2 is enhanced in the MI-heart. Moreover, increased levels of NCOA4, beclin-1, and LC3-II/LC3-I, along with decreased p62, suggest enhanced ferritinophagy in MI-induced hearts. Nrf2 was pharmacologically suppressed in differentiated H9c2 cardiomyocytes to explore its potential role in MI pathophysiology. Remarkably, this inhibition rescued CoCl 2 -induced hypoxic stress, as evidenced by the decreased ferritinophagy and apoptotic cell death.
Conclusion and Implications
Augmented Nrf2-transcriptional activity disrupts iron metabolism through the hepcidin/ferroportin axis, leading to iron sequestration and promoting ferritinophagy within cardiomyocytes, thereby exacerbating MI.
