The underlying pathological mechanism of ferroptosis in the development of cardiovascular disease

Abstract

Cardiovascular diseases (CVDs) have been attracting the attention of academic society for decades. Numerous researchers contributed to figuring out the core mechanisms underlying CVDs. Among those, pathological decompensated cellular loss posed by cell death in different kinds, namely necrosis, apoptosis and necroptosis, was widely regarded to accelerate the pathological development of most heart diseases and deteriorate cardiac function. Recently, apart from programmed cell death revealed previously, ferroptosis, a brand-new cellular death identified by its ferrous-iron-dependent manner, has been demonstrated to govern the occurrence and development of different cardiovascular disorders in many types of research as well. Therefore, clarifying the regulatory function of ferroptosis is conducive to finding out strategies for cardio-protection in different conditions and improving the prognosis of CVDs. Here, molecular mechanisms concerned are summarized systematically and categorized to depict the regulatory network of ferroptosis and point out potential therapeutic targets for diverse cardiovascular disorders.

Keywords: cardiovascular disease; ferroptosis; mechanism; metabolism; pathology.

FIGURE 1

The anti-oxidative system inhibits ferroptosis to protect against cardiovascular disease by eliminating oxidative stress. The figure shows the protective effects of the SOD family, catalase, Trx recycles, system Xc^–-GSH-GPX4 pathway, FSP1-CoQ10-NAD(P)H pathway, and tocopherol on the elimination of ROS and reducing the conversion to lipid peroxide, such as toxic MDA and 4-HNE. ROS, reactive oxygen species; SOD, superoxide dismutase; FSP, ferroptosis suppressor protein; CoQ, coenzyme Q; GSH, glutathione; GSSG, oxidized glutathione; GSR, glutathione reductase; GPX, glutathione peroxidase; 4-HNE, 4-hydroxynonenal; MDA, malondialdehyde; TPX, thioredoxin peroxidase; Trx red, reduced thioredoxin; Trx ox, oxidized thioredoxin; PUFA, polyunsaturated fatty acid.

FIGURE 2

The role of DAMPs released from ferroptotic CMs in inflammation. The release of DAMPs from ferroptotic cells activates the downstream NF-κB inflammatory pathway through the TLR and RAGE receptors of inflammatory cells, leading to the production of inflammatory factors (e.g., NF-κB, IL-6, IFN-γ, TNF-α, and IL-1β) which were also produced due to the increase of ROS to induce more CMs ferroptosis. In addition, ECs respond to DAMPs via TLR4 receptors and release chemokines to promote more inflammatory cells entering the myocardial microenvironment. CM, cardiomyocyte; ROS, reactive oxygen species; DAMP, damage-associated molecular pattern; HMGB, high mobility group box; RAGE, receptor for advanced glycation end products; TLR, Toll-like receptors; MEK, mitogen-activated protein kinase kinase; NF-κB, nuclear factor-kappa B; NLRP, NOD-like receptor thermal protein domain associated protein; NLRC, NLR family CARD domain containing; MyD88, myeloid differentiation factor 88; IL, interleukin; TRIF, TIR-domain-containing adapter-inducing interferon-β; IFN, interferon; EC, endothelial cell.

FIGURE 3

Immune cells involved in the regulation of CMs ferroptosis. This figure summarizes macrophages and T cells activity regulating the ferroptosis following cardiac injury. The cross-talk between these immune cells and CMs depends on various inflammatory factors and exosomes. DC, dendritic cell; CM, cardiomyocyte; IL, interleukin; TNF, tumor necrosis factor; IFN, interferon; TGF, transforming growth factor; CCR, C-C motif chemokine receptor 2.

FIGURE 4

The role of glucose and fatty acid metabolic disorders in the regulatory network of ferroptosis of CVDs. The long-chain fatty acid is activated and transformed into long-chain fatty acyl-CoA with the catalytic activity of ACSL/ACSVL. The long-chain fatty acyl-CoA combines with carnitine and enters fatty acid β-oxidation in the mitochondrial matrix with help of CPT1, CPT2, and CACT. Then acetyl-CoA from the β-oxidation cycle, anaerobic glycolysis, and glutaminolysis gather to strengthen the metabolism of the TCA cycle in mitochondrial matrix, which activates downstream OXPHOS and ROS, eventually resulting in cellular ferroptosis. CVDs, cardiovascular diseases; ACSL, long-chain acyl-CoA synthases; ACSVL, very long-chain acyl-CoA synthases; CoA, coenzyme A; CPT1, carnitine palmitoyltransferase1; CPT2, carnitine palmitoyltransferase2; CACT, carnitine-acylcarnitine translocase; OXPHOS, oxidative phosphorylation; ROS, reactive oxygen species.

FIGURE 5

Interaction of intracellular iron metabolism and ferroptosis. Fe³⁺ and Tf bind to form Fe³⁺-Tf complex and enter the cell by means of TfR1 via endocytosis. In endosomes, Fe³⁺ is liberated from Tf and catalyzed by STEAP to Fe²⁺, while Tf is released extracellularly by exocytosis. The process Fe²⁺ released from endosomes or absorbed into the cells depends on DMT1. In mitochondria, the utilization of Fe²⁺ is mainly the synthesis of Fe–S clusters and heme, which can be degraded by Hmox1 to regenerate Fe²⁺. Excess Fe²⁺ can store in ferritin by converting into Fe³⁺, while ferritinophagy can re-release free iron. Intracellular Fe²⁺ can also be exported through FP1. The above processes participate in the regulation of intracellular Fe²⁺ content to control Fenton reaction, thereby regulating the occurrence of ferroptosis. FP1, ferroportin1; DMT1, divalent metal transporter 1; Tf, transferrin; TfR1, transferrin receptor 1; Hmox1, Heme oxygenase 1; STEAP3, six-transmembrane epithelial antigen of the prostate 3.