Activation of NRF2/FPN1 pathway attenuates myocardial ischemia–reperfusion injury in diabetic rats by regulating iron homeostasis and ferroptosis

Abstract

In patients with ischemic heart disease, myocardial ischemia–reperfusion injury (IRI) can aggravate their condition even worse, and diabetes increases their risk of myocardial IRI. Pathological pathways of common diseases and surgical operations like diabetes, obesity, coronary artery angioplasty, and heart transplantation entail disorders of iron metabolism. Ferroportin1 (FPN1) is the only mammalian protein associated with iron release and thus plays a vital role in iron homeostasis, while nuclear factor E2-related factor 2 (NRF2) controls the transcription of FPN1. Since the NRF2/FPN1 pathway may play a favorable role in the therapy of diabetic myocardial IRI, this work investigated the possible mechanism. In this study, we investigated the effects of ferroptosis in STZ-induced diabetic rats following myocardial IRI in vivo, and its alteration in glucose and hypoxia/reoxygenation-induced cardiomyocytes injury in vitro. Rats and H9c2 cardiomyocytes were randomly divided into 6 groups and treated with sulforaphane and erastin besides the establishment of diabetic myocardial IRI and hyperglycemic hypoxia-reoxygenation models. Cardiac functional and structural damage were detected by Evans blue/TTC double staining, echocardiography, HE staining, and serological indices. CCK-8 assay and ROS production were used to measure cardiomyocyte viability and oxidative stress level. Additionally, the changes in cell supernatant levels of Fe2+, SOD, MDA, and mRNA and protein expression of ferroptosis marker proteins confirmed the beneficial effects of the NRF2/FPN1 pathway on diabetic myocardial IRI related to iron metabolism and ferroptosis. Overall, these findings suggest that iron homeostasis-related ferroptosis plays an important role in aggravating myocardial IRI in diabetic rats, and NRF2/FPN1 pathway-mediated iron homeostasis and ferroptosis might be a promising therapeutic target against myocardial IRI in diabetes.

Ferroptosis and Acute Kidney Injury (AKI): Molecular Mechanisms and Therapeutic Potentials

“…Fan et al reported that overexpression of Nrf2 could up-regulate SLC7A11, thereby inhibiting the cell ferroptosis ( Fan et al, 2017 ). Tian et al found Nrf2 attenuated myocardial ischemia-reperfusion injury in diabetic rats via blocking ferroptosis ( Tian et al, 2022 ). In addition, Sun et al reported that the p62/Keap1/Nrf2 axis was activated under the stimulation of ferroptosis inducers, causing the activation and transcription of HO-1 and FTH-1 and finally decreasing the sensitivity to ferroptosis in cells ( Sun et al, 2016 ).…”

Hydrogen Sulfide Inhibits Ferroptosis in Cardiomyocytes to Protect Cardiac Function in Aging Rats

“…However, our study also demonstrated the effects of H 2 S on the expressions of FTH and FPN1 in cardiomyocytes. FPN1 is the only known mammalian iron export protein, and FTH is the main iron storage protein in cells (Tian et al, 2021;Wang et al, 2022). Increasing FPN1 expression and inhibiting the degradation of FTH reduce intracellular iron accumulation (Gao et al, 2016;Hou et al, 2016).…”

“…Ferroptosis differs from apoptosis, necroptosis, and autophagy in several aspects (Dixon et al, 2012;Stockwell et al, 2017). Ferroptosis plays critical roles in cardiomyopathy, myocardial infarction, ischemia/ reperfusion injury, and heart failure (Park et al, 2019;Tang et al, 2021;Tian et al, 2021;Zheng et al, 2021;Lin et al, 2022).…”

Edaravone Ameliorates Cerebral Ischemia–Reperfusion Injury by Downregulating Ferroptosis <i>via</i> the Nrf2/FPN Pathway in Rats

“…7) FPN is the only known intracellular iron transport export protein, and Nrf2 can inhibit ferroptosis by upregulating FPN levels and suppressing iron overload. 8) Edaravone is an important antioxidant that plays a protective role in ischemic stroke and significantly improves clinical symptoms. Clinical and experimental studies have shown that edaravone acts as a free radical scavenger, scavenging many free radicals, such as hydroxyl radicals and peroxyl radicals, thereby inhibiting lipid peroxidation and reducing CIRI.…”