Potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in individuals with diabetes

Abstract

Diabetes and its complications are major diseases that affect human health. Diabetic cardiovascular complications such as cardiovascular diseases (CVDs) are the major complications of diabetes, which are associated with the loss of cardiovascular cells. Pathogenically the role of ferroptosis, an iron-dependent cell death, and cuproptosis, a copper-dependent cell death has recently been receiving attention for the pathogenesis of diabetes and its cardiovascular complications. How exposure to environmental metals affects these two metal-dependent cell deaths in cardiovascular pathogenesis under diabetic and nondiabetic conditions remains largely unknown. As an omnipresent environmental metal, cadmium exposure can cause oxidative stress in the diabetic cardiomyocytes, leading to iron accumulation, glutathione depletion, lipid peroxidation, and finally exacerbate ferroptosis and disrupt the cardiac. Moreover, cadmium-induced hyperglycemia can enhance the circulation of advanced glycation end products (AGEs). Excessive AGEs in diabetes promote the upregulation of copper importer solute carrier family 31 member 1 through activating transcription factor 3/transcription factor PU.1, thereby increasing intracellular Cu⁺ accumulation in cardiomyocytes and disturbing Cu⁺ homeostasis, leading to a decline of Fe-S cluster protein and reactive oxygen species accumulation in cardiomyocytes mitochondria. In this review, we summarize the available evidence and the most recent advances exploring the underlying mechanisms of ferroptosis and cuproptosis in CVDs and diabetic cardiovascular complications, to provide critical perspectives on the potential pathogenic roles of ferroptosis and cuproptosis in cadmium-induced or exacerbated cardiovascular complications in diabetic individuals.

Keywords: cadmium; cardiovascular diseases; cuproptosis; diabetes; diabetic cardiomyopathy; ferroptosis.

Figure 1

Potential role of cadmium in exacerbating cardiovascular complications in individuals with diabetes. Cadmium exposure in individuals with diabetes results in hyperglycemia, ceramide accumulation, and an increase in the FFA oxidation, proinflammatory cytokines as well as generation of ROS. The ROS activate several pathways involved in the pathogenesis of diabetic cardiovascular complications, including inflammation, disrupting DNA repair, oxidative stress, apoptosis, and cell death. FFA, free fatty acid; ROS, reactive oxygen species.

Figure 2

Schematic model of ferroptosis and molecular mechanisms of cadmium-exacerbated ferroptosis in diabetic cardiomyocytes. Molecular mechanisms of ferroptosis and related signaling pathways, which mainly include iron metabolism, GSH and GPX4, and lipid peroxidation. (1) Iron uptake via the transferrin receptor 1 (TfR1) or degradation of ferritin iron stores increases the labile iron pool, thereby cells are susceptible to ferroptosis via the formation of lipid hydroperoxides through the Fenton-like reaction. (2) Cystine-glutamate antiporter system Xc- regulates cysteine and GSH availability. GPX4 utilizes GSH to reduce lipid hydroperoxides, thereby preventing lipid peroxidation chain reactions. (3) The PUFA-PLs that are derived from PUFA-CoA by LPCAT3 and PUFA by ACSL4, respectively, are the main causative of lipid peroxidation. Cadmium exposure can cause oxidative stress in the diabetic cardiomyocytes, leading to iron accumulation, GSH depletion, lipid peroxidation, and finally exacerbate ferroptosis and disrupt the cardiac. In addition, Nrf2 up-regulation due to cadmium-induced oxidative stress can increase HO-1 expression to regulate iron hemostasis. GSH, reduced glutathione; GPX4, glutathione peroxidase 4; system Xc-, cystine–glutamate antiporter; PUFAs, polyunsaturated fatty acids; PUFA-CoA, PUFA coenzyme A; PUFA-PL, phospholipid PUFA; Nrf2, nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase.

Figure 3

Schematic model of cuproptosis and molecular mechanisms of cadmium-induced cuproptosis in diabetic cardiomyocytes. Elesclomol binds extracellular copper (Cu²⁺) and transports it to intracellular compartments. Besides, copper ion channels SLC31A1 and ATP7B regulate the accumulation of Cu⁺ by mediating the entry and exocytosis of Cu⁺, respectively. Afterward, regulate cuproptosis sensitivity by affecting intracellular Cu⁺ levels. On the one hand, Cu⁺ binds to lipoylated mitochondrial enzymes in the TCA cycle such as DLAT, inducing the aggregation of these proteins. On the other hand, FDX1 as an upstream regulator of protein lipoylation reduces Cu²⁺ to Cu⁺, and with LIAS facilitates the aggregation of mitochondrial proteins and loss of Fe–S cluster proteins. Cadmium-induced hyperglycemia can enhance circulating AGEs. Excessive AGEs in diabetes promote the upregulation of copper importer SLC31A1 through ATF3/SPI1, thereby increasing intracellular Cu⁺ accumulation in cardiomyocytes and disturbing Cu⁺ homeostasis, leading to a decline of Fe–S cluster protein and ROS accumulation in cardiomyocytes mitochondria. ATP7B, ATPase copper transporting beta; SLC31A1, solute carrier family 31 member 1; Fe–S, iron-sulfur; FDX1, ferredoxin 1; TCA, tricarboxylic acid; DLAT, dihydrolipoamide S-acetyltransferase; LA-DLAT, lipoylated DLAT; LIAS, lipoyl synthase; AGEs, Advanced Glycosylation End Products.