Ferroptosis as a novel therapeutic target for cardiovascular disease

Abstract

Cell death is an important component of the pathophysiology of cardiovascular disease. An understanding of how cardiomyocytes die, and why regeneration of cells in the heart is limited, is a critical area of study. Ferroptosis is a form of regulated cell death that is characterized by iron overload, leading to accumulation of lethal levels of lipid hydroperoxides. The metabolism of iron, lipids, amino acids and glutathione tightly controls the initiation and execution of ferroptosis. Emerging evidence shows that ferroptosis is closely associated with the occurrence and progression of various diseases. In recent years, ferroptosis has been found to play critical roles in cardiomyopathy, myocardial infarction, ischemia/reperfusion injury, and heart failure. This article reviews the mechanisms by which ferroptosis is initiated and controlled and discusses ferroptosis as a novel therapeutic target for various cardiovascular diseases.

Keywords: cardiomyopathy; ferroptosis; heart failure; ischemia/reperfusion injury; myocardial infarction.

Figure 1

Schematic representation of the mechanism of ferroptosis. Ferroptosis is an iron-dependent form of regulated cell death mediated by lipid peroxidation of cellular membranes. Fe³⁺ imported through the transferrin receptor is converted to Fe²⁺ in endosomes and released from endosome by divalent metal transporter 1 (DMT1). Fenton reaction converts Fe²⁺ into Fe³⁺, which induces lipid peroxidation by activating lipoxygenases. Glutathione peroxidase 4 (GPX4) is the major endogenous mechanism to suppress lipid peroxidation. High extracellular concentrations of glutamate inhibit system X_c^-, which imports cystine by exchanging intracellular glutamate for extracellular cystine. Cystine is subsequently converted to cysteine, which generates glutathione (GSH), a cofactor for GPX4. Erastin, glutamate, and sorafenib are inhibitors of system X_c^-; RSL3, ML162 and FIN56 are inhibitors of GPX4.

Figure 2

Ferroptosis is a potential therapeutic target for cardiovascular diseases. (A) DXZ and Fer-1 protect against DOX-induced cardiomyopathy by suppressing lipid peroxidation, reducing ferroptosis, and maintaining mitochondrial function; (B) Lip-1 inhibits ferroptosis by increasing GPX4 expression and decreasing ROS levels, thus reducing myocardial infarct size and ischemia/reperfusion injury. (C) mTOR regulates cellular iron transport and prevents iron overload in cardiomyocytes, thus suppressing ferroptosis and reducing ischemia/reperfusion injury. DOX, doxorubicin; DXZ, dexrazoxane; Fer-1, ferrostatin-1; GPX4, glutathione peroxidase 4; Lip-1, liproxstatin-1; mTOR, mechanistic target of rapamycin; ROS, reactive oxygen species.