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Review
. 2021 Nov 11:9:733908.
doi: 10.3389/fcell.2021.733908. eCollection 2021.

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases

Meng-Yi Luo  1   2 , Jian-Hui Su  1   2 , Shao-Xin Gong  3 , Na Liang  4 , Wen-Qian Huang  1   2 , Wei Chen  1   2 , Ai-Ping Wang  1   2 , Ying Tian  1
Affiliations
Review

Ferroptosis: New Dawn for Overcoming the Cardio-Cerebrovascular Diseases

Meng-Yi Luo et al. Front Cell Dev Biol. .

Abstract

The dynamic balance of cardiomyocytes and neurons is essential to maintain the normal physiological functions of heart and brain. If excessive cells die in tissues, serious Cardio-Cerebrovascular Diseases would occur, namely, hypertension, myocardial infarction, and ischemic stroke. The regulation of cell death plays a role in promoting or alleviating Cardio-Cerebrovascular Diseases. Ferroptosis is an iron-dependent new type of cell death that has been proved to occur in a variety of diseases. In our review, we focus on the critical role of ferroptosis and its regulatory mechanisms involved in Cardio-Cerebrovascular Diseases, and discuss the important function of ferroptosis-related inhibitors in order to propose potential implications for the prevention and treatment of Cardio-Cerebrovascular Diseases.

Keywords: cardio-cerebrovascular disease; ferroptosis; inflammation; iron; lipid peroxidation.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Mechanism of ferroptosis in myocardial infarction (MI), heart failure (HF), diabetic cardiomyopathy (DCM) and atherosclerosis (AS). MI: Under the stimulation of ischemia and hypoxia, excessive free iron releases via up-regulation of heme oxygenase 1 (Hmox1), promoting ferroptosis and eventually causing I/R injury, myocardial remodeling and myocardial cell rupture. HF: Stimulated by pressure and volume overload, labile iron pool (LIP) formation increases, leading to iron overload and the occurrence of ferroptosis, and then causing myocardial edema, arrhythmia and cardiomyocyte cell death. DCM: In the circumstance of hyperglycemia, free iron increases and glucolipotoxicity induces ferroptosis, triggering myocardial fibrosis, and myocardial hypertrophy. AS: When there exists lipid metabolism disturbance, iron overload and oxidized low-density lipoprotein (ox-LDL) induce lipid peroxidation that triggers ferroptosis, finally causing endothelial dysfunction and plaque instability.
FIGURE 2
FIGURE 2
Mechanism of ferroptosis in hypertension and ischemic stroke. The decrease of glutathione peroxidase 4 (GPX4), glutathione (GSH), tau protein, and the increase of lipoxygenase (LOX), blood-brain barrier (BBB) permeability, can lead to the occurrence of ferroptosis. LOX is involved in hypertensive brain injury, tau protein and BBB permeability are involved in ischemic stroke.
FIGURE 3
FIGURE 3
Schematic representation of the mechanism of ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death mediated by iron overload and lipid peroxidation of cellular membranes. Fe3+ imported through the transferrin receptor is converted to Fe2+ in endosomes and released from endosome by divalent metal-ion transporter 1 (DMT1). Fenton reaction converts Fe2+ into Fe3+, which induces lipid peroxidation. GPX4 is the major endogenous mechanism to suppress lipid peroxidation. High extracellular concentrations of glutamate (Glu) inhibit system Xc −, which imports cystine (Cys) by exchanging intracellular Glu for extracellular Cys. Cys is subsequently converted to cysteine, which generates GSH, a cofactor for GPX4.
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References

    1. Abdalkader M., Lampinen R., Kanninen K. M., Malm T. M., Liddell J. R. (2018). Targeting Nrf2 to Suppress Ferroptosis and Mitochondrial Dysfunction in Neurodegeneration. Front. Neurosci. 12, 466. 10.3389/fnins.2018.00466 - DOI - PMC - PubMed
    1. Abdelwahid E., Stulpinas A., Kalvelyte A. (2017). Effective Agents Targeting the Mitochondria and Apoptosis to Protect the Heart. Cpd 23 (8), 1153–1166. 10.2174/1381612822666161229150120 - DOI - PubMed
    1. Alim I., Caulfield J. T., Chen Y., Swarup V., Geschwind D. H., Ivanova E., et al. (2019). Selenium Drives a Transcriptional Adaptive Program to Block Ferroptosis and Treat Stroke. Cell 177 (5), 1262–1279. e25. 10.1016/j.cell.2019.03.032 - DOI - PubMed
    1. Anandhan A., Dodson M., Schmidlin C. J., Liu P., Zhang D. D. (2020). Breakdown of an Ironclad Defense System: The Critical Role of NRF2 in Mediating Ferroptosis. Cel Chem. Biol. 27 (4), 436–447. 10.1016/j.chembiol.2020.03.011 - DOI - PMC - PubMed
    1. Angeli J. P. F., Shah R., Pratt D. A., Conrad M. (2017). Ferroptosis Inhibition: Mechanisms and Opportunities. Trends Pharmacological Sciences 38 (5), 489–498. 10.1016/j.tips.2017.02.005 - DOI - PubMed

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