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.

Keywords: cardioprotection; ferroptosis; ischemia; liproxstatin-1; oxidative stress; reperfusion.

Figure 1

Schematic diagram of the main contributory oxidative stress-related factors involved in the pathophysiology of myocardial damage due to ischemia-reperfusion. eNOS, endothelial nitric oxide synthase; Fe²⁺, ferrous iron; FT, ferritin; H₂O₂: hydrogen peroxide; mPTP, mitochondrial permeability transition pore; NADPH ox, reduced nicotine adenine dinucleotide phosphate oxidase; NO, nitric oxide; O₂^•−, superoxide radical anion; ^•OH, hydroxyl radical; ONOO⁻, peroxynitrite anion.

Figure 2

Molecular mechanisms of the deleterious effects of ferroptosis and proposed sites of protective action of liproxstatin-1. ARE, antioxidant response elements; DMT1, divalent metal transporter; Fe²⁺, ferrous iron; Fe³⁺, ferric iron; GPX4, glutathione peroxidase 4; GR, glutathione reductase; HO-1, heme oxygenase 1; H₂O₂, hydrogen peroxide; LOH, lipid alcohols; LOOH, lipid hydroperoxides; LOX, lipoxygenase; LTCC, L-type calcium channel; mPTP, mitochondrial permeability transition pore; Nrf2, nuclear factor-erythroid 2-related factor 2; NCOA4, nuclear receptor coactivator 4; O₂^•−, superoxide radical; ^•OH, hydroxyl radical; PUFA, poly-unsaturated fatty acids; SOD, superoxide dismutase; TF, transferrin; TfR1, transferrin receptor.