Targeting Ferroptosis against Ischemia/Reperfusion Cardiac Injury

Abstract

Ischemic heart disease is a leading cause of death worldwide. Primarily, ischemia causes decreased oxygen supply, resulting in damage of the cardiac tissue. Naturally, reoxygenation has been recognized as the treatment of choice to recover blood flow through primary percutaneous coronary intervention. This treatment is the gold standard therapy to restore blood flow, but paradoxically it can also induce tissue injury. A number of different studies in animal models of acute myocardial infarction (AMI) suggest that ischemia-reperfusion injury (IRI) accounts for up to 50% of the final myocardial infarct size. Oxidative stress plays a critical role in the pathological process. Iron is an essential mineral required for a variety of vital biological functions but also has potentially toxic effects. A detrimental process induced by free iron is ferroptosis, a non-apoptotic type of programmed cell death. Accordingly, efforts to prevent ferroptosis in pathological settings have focused on the use of radical trapping antioxidants (RTAs), such as liproxstatin-1 (Lip-1). Hence, it is necessary to develop novel strategies to prevent cardiac IRI, thus improving the clinical outcome in patients with ischemic heart disease. The present review analyses the role of ferroptosis inhibition to prevent heart IRI, with special reference to Lip-1 as a promising drug in this clinicopathological context.

Insight into Crosstalk between Ferroptosis and Necroptosis: Novel Therapeutics in Ischemic Stroke

“…Another research has indicated that ubiquitin-specific protease 22, a member of the deubiquitinase family, protects against myocardial ischemia-reperfusion injury via the SIRT1-p53/SLC7A11-dependent inhibition of ferroptosis-induced cardiomyocyte death [ 106 ]. These findings highlight that targeting ferroptosis serves as a cardioprotective strategy for cardiomyopathy prevention [ 107 , 108 ]. The similar research in the central nervous system indicated that ferroptosis may be also an emerging target in CIRI [ 109 ].…”

Joint Cardioprotective Effect of Vitamin C and Other Antioxidants against Reperfusion Injury in Patients with Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention

“…Furthermore, during the MIRI process, iron mobilization occurs, which increases the concentrations of the labile iron pool that, in turn, can promote the occurrence of Fenton reactions and the production of ·OH ( Figure 1 ). Several pathways can contribute to an increase in the cytosolic free iron that has been described in MIRI, such as ferritinophagy [ 34 ], polyol pathway [ 35 ], myocardial hemorrhage [ 36 ], Fe-S cluster [ 37 ], and heavy ferritin chain [ 38 ], all of which would finally induce ferroptosis in cardiac tissue [ 39 ].…”

“…Although progress has been made in therapies, there are multiple pathways that favor an increase in the infarct size, including some that may not have been discovered yet. Cardiomyocyte cell death through apoptosis, necrosis, pyroptosis, autophagy, or ferroptosis is a central target to reduce infarct size [ 14 , 39 ]. However, there is still much to be elucidated, and the results are not of total consensus.…”

“…Finally, a couple of years ago, some authors hypothesized that a multitarget therapy is necessary to be able to fully achieve a benefit in patients subjected to cardiac reperfusion, since AMI is a multifactorial process, wherein cardiomyocytes die through various pathways, such as apoptosis, necrosis, autophagy, and necroptosis [ 11 ], and where, with the passing of time, the list is enlarged, describing new pathways that could be triggering cell death after the reperfusion injury, such as ferroptosis [ 39 , 89 ] and pyroptosis [ 90 ]. Furthermore, not only cardiomyocytes are affected, but also other heart cell types, such as fibroblasts, immune cells, endothelial cells, and platelets [ 11 ], and targeting only one mechanism at a time may be insufficient to produce a strong and robust effect in clinical situations where many uncontrolled variables usually coexist.…”

Ferroptosis: Opportunities and Challenges in Myocardial Ischemia‐Reperfusion Injury

“…In recent years, ferroptosis has received extensive attention because it participates in the pathophysiological processes of tumor formation, kidney-related diseases, neurodegenerative diseases, stroke, and other diseases [ 4 ]. The occurrence and development of ferroptosis are closely related to the pathological process of myocardial cells, with ferroptosis participating in the pathogenic mechanisms of MIRI [ 5 ]. Ferritin was found to accumulate at the myocardial scar area of the left anterior descending coronary artery of mice in the ischemia-reperfusion injury(IRI) model after 30 min of ligation [ 6 ].…”