Ferroptosis, a Regulated Form of Cell Death, as a Target for the Development of Novel Drugs Preventing Ischemia/Reperfusion of Cardiac Injury, Cardiomyopathy and Stress-Induced Cardiac Injury

Abstract

The hospital mortality in patients with ST-segment elevation myocardial infarction (STEMI) is about 6% and has not decreased in recent years. The leading cause of death of these patients is ischemia/reperfusion (I/R) cardiac injury. It is quite obvious that there is an urgent need to create new drugs for the treatment of STEMI based on knowledge about the pathogenesis of I/R cardiac injury, in particular, based on knowledge about the molecular mechanism of ferroptosis. In this study, it was demonstrated that ferroptosis is involved in the development of I/R cardiac injury, antitumor drug-induced cardiomyopathy, diabetic cardiomyopathy, septic cardiomyopathy, and inflammation. There is indirect evidence that ferroptosis participates in stress-induced cardiac injury. The activation of AMPK, PKC, ERK1/2, PI3K, and Akt prevents myocardial ferroptosis. The inhibition of HO-1 alleviates myocardial ferroptosis. The roles of GSK-3β and NOS in the regulation of ferroptosis require further study. The stimulation of Nrf2, STAT3 prevents ferroptosis. The activation of TLR4 and NF-κB promotes ferroptosis of cardiomyocytes. MiR-450b-5p and miR-210-3p can increase the tolerance of cardiomyocytes to hypoxia/reoxygenation through the inhibition of ferroptosis. Circ_0091761 RNA, miR-214-3p, miR-199a-5p, miR-208a/b, miR-375-3p, miR-26b-5p and miR-15a-5p can aggravate myocardial ferroptosis.

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“…Myocardial infarction promoted a reduction in SOD, catalase, and GPx activity, and increased the malondialdehyde (MDA) level. MI induced ferroptosis [86]. Exendin-4 abolished these alterations [81].…”

“…There are five main forms of regulated cardiomyocyte death: apoptosis, necroptosis, pyroptosis, autophagy, and ferroptosis [85][86][87][88][89]. There is a sixth form of cell death: paraptosis [90].…”

“…It has been found that remote postconditioning, adaptation to hypoxia, and cold increased cardiac tolerance to I/R [86,141,149]. The question of whether GLP-1 and the GLP1R are involved in the cardioprotective effect of remote postconditioning and adaptation to hypoxia and cold remains to be studied.…”