Counteraction of Myocardial Ferritin Heavy Chain Deficiency by Heme Oxygenase-1.
Sarah E MachadoDaryll SpanglerDelores A StacksVictor Darley-UsmarGloria A BenavidesMin XieJózsef BallaAbolfazl ZarjouPublished in: International journal of molecular sciences (2022)
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.
Keyphrases
- left ventricular
- cell proliferation
- acute myocardial infarction
- pi k akt
- aortic stenosis
- poor prognosis
- ejection fraction
- heart failure
- hypertrophic cardiomyopathy
- cardiac resynchronization therapy
- signaling pathway
- mitral valve
- transcription factor
- public health
- cell death
- oxidative stress
- left atrial
- healthcare
- genome wide
- atrial fibrillation
- radiation therapy
- long non coding rna
- acute coronary syndrome
- aortic valve
- dna methylation
- replacement therapy
- binding protein
- human health