Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1

Abstract

Given the abundance of heme proteins (cytochromes) in the mitochondrion, it is evident that a meticulously orchestrated iron metabolism is essential for cardiac health. Here, we examined the functional significance of myocardial ferritin heavy chain (FtH) in a model of acute myocardial infarction. We report that FtH deletion did not alter either the mitochondrial regulatory and surveillance pathways (fission and fusion) or mitochondrial bioenergetics in response to injury. Furthermore, deletion of myocardial FtH did not affect cardiac function, assessed by measurement of left ventricular ejection fraction, on days 1, 7, and 21 post injury. To identify the modulated pathways providing cardiomyocyte protection coincident with FtH deletion, we performed unbiased transcriptomic analysis. We found that following injury, FtH deletion was associated with upregulation of several genes with anti-ferroptotic properties, including heme oxygenase-1 (HO-1) and the cystine/glutamate anti-porter (Slc7a11). These results suggested that HO-1 overexpression mitigates ferroptosis via upregulation of Slc7a11. Indeed, using transgenic mice with HO-1 overexpression, we demonstrate that overexpressed HO-1 is coupled with increased Slc7a11 expression. In conclusion, we demonstrate that following injury, myocardial FtH deletion leads to a compensatory upregulation in a number of anti-ferroptotic genes, including HO-1. Such HO-1 induction leads to overexpression of Slc7a11 and protects the heart against ischemia-reperfusion-mediated ferroptosis, preserves mitochondrial function, and overall function of the myocardium.

Ferritin heavy chain participated in ameliorating 3-nitropropionic acid-induced oxidative stress and apoptosis of goose follicular granulosa cells

“…Deletion of myocardial FHC was responsible for compensatory upregulation of some iron resistance genes comprising heme oxygenase ( HO-1 ). During this process, HO-1 induced solute carrier family 7 member 11 ( SLC7A11 ) overexpression, protected the heart from ischemia reperfusion-mediated ferroptosis, and safeguarded mitochondrial function ( Machado et al, 2022 ). Cheng et al reported stimulated HO-1 in rat glomerular mesangial cells to enhance their resistance to hydrogen peroxide.…”

New Insights into the Role of Ferroptosis in Cardiovascular Diseases

“…Furthermore, Ma et al [ 132 ] reported that the expression of antioxidant sirtuin 1 (SIRT1) in the heart tissue was repressed after I/R damage, and SIRT1 overexpression was shown to lower the extent of I/R injury-related ferroptotic cell death via p53/SLC7A11 axis. Machado et al [ 133 ] reported that during cardiac I/R injury, ferritin shortage activates the synthesis of many antiferroptotic proteins, including HO-1. In turn, HO-1 upregulation leads to SLC7A11 induction and hence to GSH generation which reduces ferroptosis and preserves heart function.…”

“…In turn, HO-1 upregulation leads to SLC7A11 induction and hence to GSH generation which reduces ferroptosis and preserves heart function. Nevertheless, HO-1 upregulation may be a double-edged sword since it causes heme degradation and the release of Fe 2+ which promotes ferroptosis [ 133 ]. Finally, it has to be noted that ubiquitination and some non-coding RNAs have also been shown to play a role in ferroptosis induced by I/R injury [ 134 ].…”

Inflammation, dysregulated iron metabolism, and cardiovascular disease

“…, Baba et al (2018, showed that inducing ferroptosis in cardiomyocytes significantly increased cell death and ROS production, which was alleviated by treatment with Ferrostatin-1, an ROS scavenger. Machado et al (2022), in 2022 examined if FHC deletion in cardiomyocytes altered mitochondrial dynamics and cardiac function. Interestingly, they found that deletion of FHC did not affect mitochondrial or overall cardiac function, but rather the expression of genes related to glutathione metabolism, including SLC7a11 and heme oxygenase 1 (HO-1).…”