Research progress on iron homeostasis regulation and heart-related diseases

Yang Yang,Qi Feng,Huang Sun,Yi Zhao,Hui-Jie Hao,Xing Chen*

1Translational Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China.2School of History, Zhengzhou University,Zhengzhou 450001, China.3Research Institute of Nephrology,Zhengzhou University,The First Affiliated Hospital of Zhengzhou University,Zhengzhou 450052,China.4Tianjin Key Laboratory of Retinal Functions and Diseases,Tianjin Medical University,Tianjin 300384,China.

Yang Yang and Qi Feng are co-first authors of this paper.

Abstract Iron is an indispensable trace element in mammals and performs several important physiological functions in the body.Dynamic equilibrium in iron metabolism exists.Iron uptake, storage, and output are in equilibrium as well.Several laboratory animal models have shown that iron deficiency and deposition can lead to a variety of functional disorders.Cardiac diseases caused by iron deposition in laboratory animal models are caused by abnormal oxidative stress, electrophysiological changes, iron metabolism-related gene defects, myocardial cell apoptosis, fibrosis, ferroptosis, and other causes.This review discusses the causes of heart disease related to iron deposition in laboratory animal models to illustrate further the impact of effective iron removal therapy on cardiac disease associated with iron deposition.In addition, this review demonstrates the possibility of elucidating the precise molecular mechanism of iron abnormality in heart diseases in experimental animal models and the feasibility of using iron abnormality as a target for developing new therapeutic drugs for the treatment of heart disease.

Keywords:iron;heart-related diseases; experimental animal model;iron removal treatment

Background

Iron metabolism homeostasis plays an important role in cell homeostasis regulation.The disorder of iron ion metabolism in electron transport chain function maintenance, oxygen transport, and other processes will lead to a series of serious diseases.The heart is an energy-consuming organ in which iron metabolism plays an important role.This review concluded the causes of heart disease related to iron deposition in animal models to illustrate further the impact of effective iron removal therapy on cardiac disease associated with iron deposition.In addition, this review demonstrates the possibility of elucidating the precise molecular mechanism of iron abnormality in heart diseases and the feasibility of using iron abnormality as a target for developing new therapeutic drugs to treat heart disease.

Iron is an indispensable trace element in mammals and exists in the trivalent form in the natural environment.However, many animals cannot obtain enough iron to maintain their physiological functions because of the poor solubility and low bioavailability of iron.Moreover,iron is also one of the essential trace elements in the human body; the amount of iron in adults is about 35–45 mg/kg [1].Iron plays an important role in the electronic respiratory chain, DNA synthesis, and oxygen utilization.Its deficiency may lead to various functional disorders, such as disorders in immunity, nerve, and respiration.Most iron exists in animals as erythrocyte hemoglobin; a small amount exists in the liver,spleen,and bone marrow as ferritin or hemosiderin; and some others exist in metabolism-related enzymes involved in immune regulation.Low iron levels in the body can lead to iron deficiency, such as iron deficiency anemia.Dietary and intravenous injections can be used as an effective means for long-term iron supplementation.However, excessive iron supplementation may lead to iron deposition, which can also adversely affect animals.

The Dynamic Balance of Iron Metabolism in the Body

Iron is one of the essential trace elements in the human body; the amount of iron in adults is about 35–45 mg/kg.In mammals, iron metabolism maintains a dynamic balance of three processes: iron uptake,storage,and output[2].Mammals usually take in iron through small intestinal epithelial cells; store iron in erythrocytes, liver, and muscle fibers; and then excrete iron through feces or small intestinal epithelial cells [3].Iron homeostasis is maintained through two pathways.One pathway is regulated by hepcidin and ferroportin(FPN) to maintain iron balance on the whole level.Another pathway relies on iron-regulatory proteins and iron-responsive elements,which work together to maintain iron balance.Hepcidin is a small peptide hormone produced by liver cells, which plays a pivotal role in regulating iron homeostasis.In 2001,Pigeon et al.found that hepcidin regulates iron homeostasis in vivo [4].Hepcidin is composed of multiple small molecule polypeptides, among which the polypeptide contains 25 amino acids playing the main role.Hepcidin contains eight highly conserved cysteine residues, which are connected to hairpin structures through four intramolecular disulfide bonds [5,6].Hepcidin is synthesized by the liver and can bind to FPN to promote FPN degradation; thus, it affects iron balance by regulating the total amount of iron.When iron increases in the body, the liver will secrete more hepcidin, which results in increased FPN degradation to reduce iron formation [7].

Iron in food is oxidized, and its uptake requires duodenal cytochrome B reductase to reduce ferric ion to ferrous ion, which enters cells via ion channel protein, divalent metal transporter 1, and transfers out via FPN.Depending on the hephaestin of basolateral intestinal cells, ferrous ion is reoxidized to ferric ion, which enters the blood through transferrin (TF) in the plasma.TF binds to the transferrin receptor 1 of the target cell after it binds to iron;then,they form a complex and absorb iron through endocytosis (Figure 1)[8–10].

Figure 1 Iron transport route.Iron in food is reduced to ferrous ions by DYCTB reductase.Ferrous ion enters cells via DMT1 and is then transferred out via FPN, where it is reoxidized to ferric ion by HEPH in basolateral intestinal cells.Iron enters the blood through TF in the plasma,then binds to TFR1 and reaches the targeted cells.DYCTB, duodenal cytochrome B; DMT1, divalent metal transporter 1; FPN, ferroportin; HEPH,hephaestin; TF, through transferrin;TFR1, transferrin receptor 1.

Iron enters the cell in three ways.One way is through the labile iron pool (LIP) in the cytoplasm.Iron in the LIP is used by the cell.The other way is through cell storage as ferritin to perform related functions.The third way is to enter the mitochondria.Iron-sulfur clusters and heme are synthesized in the mitochondria and perform critical physiological functions [11].Part of iron can also be stored in mitochondrial ferritin as a reserve [12], and the mitochondrial respiratory chain is also dependent on the participation of iron.The mitochondria are the center of iron metabolism in cells, and iron is essential for maintaining mitochondrial function [13].The disorder of mitochondrial iron metabolism can seriously affect the energy metabolism of the whole cell and thus affects multiple organ functions.

Iron Homeostasis and Maintenance of Cardiac Function

The heart is one of the body’s most important organs, which continuously powers blood flow to all body parts.The animal heart consumes a lot of energy, and cardiomyocytes need to produce a large amount of ATP every day to ensure normal heart function.Iron is indispensable for this physiological process.Cardiac iron is stored in the form of ferritin and hemosiderin.A variety of heart-related diseases are closely related to iron metabolism, such as myocardial injury caused by Adriamycin (doxorubicin), because of its strong iron chelation, which catalyzes Haber-Weiss reaction to generate free radicals after combining with iron and causes myocardial injury [14].In the animal model of myocardial ischemia-reperfusion injury,the pH value of cardiomyocytes drops sharply, and the acidic environment further causes the release of iron in ferritin,reduces Fe3+to Fe2+,and generates oxygen free radicals, which results in the abnormal function of the mitochondrial respiratory chain and myocardial injury.

The destruction of iron homeostasis has a remarkable impact on myocardial cells as it further affects the structure and normal function of the heart and ultimately leads to the occurrence of animal heart disease [15].In the heart, iron deficiency and deposition will lead to serious consequences and related diseases [16].

Iron Deficiency Leads to Heart-related Diseases

Iron deficiency is common malnutrition and has been associated with many chronic diseases in animal models.Iron deficiency can lead to symptoms such as left ventricular hypertrophy or dilation,sympathetic nervous system activation,and heart failure.The increase in immune factors in the animal after heart failure further impedes iron uptake, which leads to a vicious cycle.Iron deficiency can decrease the activity of several components in the mitochondrial respiratory chain and reduce energy production, which results in serious consequences.Studies have proved that rats fed with iron-deficient feed and water for a long time have reduced body weight, ventricular hypertrophy and dilation, increased ratio of heart mass to body mass, and remarkably accelerated heart rate [17,18].The myocardial cells of the iron-deficient rat model present cell swelling, mitochondrial swelling and cleavage, disordered sarcomere arrangement, and myofibrillary fracture as observed under a microscope [17–19].In addition, Tanne et al.re-fed an iron-rich diet to mice with severe iron deficiency [19].They found that the hemoglobin in the mice returned to normal a half month later,but the hypertrophic left ventricle and papillary muscle still showed serious

degenerative changes.In practice, the two main treatments for heart failure caused by iron deficiency include oral and intravenous iron supplementation.Oral iron supplementation is more convenient than intravenous injection, but the effect is slow and easily causes adverse reactions in the gastrointestinal tract [20].Intravenous injection of iron supplements is relatively faster and safer, but the dosage and stability of iron supplements should be judged.

Iron Deposits Lead to Impaired Body Function and Heart-related Diseases

Iron deficiency often occurs during animal development.However, in the process of foodborne iron supplementation, the gastrointestinal tract is likely to be damaged by exposure to a large number of iron agents, which cause erosive injury.In the experimental model of rats,excessive iron supplementation in feed can lead to lipid peroxidation in the intestinal mucosa, mitochondrial damage in the liver, and inflammation in pregnant rats and rat embryos [21].In experimental rabbit models, feeding high-dose iron can lead to gastric ulcers and intestinal epithelial cell damage [22].In experimental mouse models,excessive iron feeding can induce oxidative stress in the liver [23].Intravenous iron supplementation also has a variety of side effects in animals.Intravenous iron is a drug precursor that is taken up by the liver or macrophages to release iron for use by cells.The stability of some injection iron agents is poor and often causes the release of iron in the blood, which induces the body's oxidative stress and increases malondialdehyde content.In rat models, iron injection resulted in substantial iron deposition in the heart, liver, and kidney and increased oxidative stress and cytokine expression.Therefore,developing iron supplements with high efficiency and low toxicity is still an urgent matter.

Long-term or high-dose iron supplementation can lead to iron deposition in the body, resulting in various animal body dysfunction.Supplementation of excessive iron (0.7 g/kg) in chicken feed can lead to oxidative stress and change the intestinal microflora structure of broilers [24].The daily addition of 1.6 g/kg iron in the feed of lambs damages the palatability of the feed,leads to plasma copper deficiency in lambs, and affects lamb growth [23].Adding 1 g/kg iron to calf feed reduces the daily gain of calves; inhibits the uptake of trace elements, such as copper and zinc, in the liver; and inhibits intestinal copper absorption [25].Newborn piglets grow fast, but the low iron levels in breast milk cannot meet the iron demands of piglets and easily causes iron deficiency.However, daily supplementation of iron dextran through intramuscular injection has certain side effects, such as remarkably reduced antioxidant and immune function [26].In addition, piglets cannot fully utilize iron supplementation, as most irons are stored in the liver and affect DNA damage repair[27].

Iron deposition remarkably damages the heart.Iron deposition can cause myocardial fibrosis, which further leads to myocardial injury and heart failure [28].Anderson et al.confirmed that using the iron-chelating agent deferoxamine can improve the symptoms of myocardial hypertrophy in mouse models [29].In another hypertensive rat model, Kumar et al.found that rats also have the phenotype of myocardial hypertrophy accompanied by iron deposition [30].The iron deposition is also an important risk factor for coronary heart disease.In mice, iron deposition also promotes atherosclerosis, and the use of iron chelators reduces iron storage in the heart muscle and improves heart function.Injection of the iron-chelating agent can cause the body to excrete iron and reduce iron deposition in the heart, but this treatment has some side effects[31].

Excessive iron content in the body will cause the metabolic imbalance of trace elements, affect the absorption of trace elements such as zinc and magnesium in the small intestine, and affect the body’s immunity.Of all the risk factors for heart disease, high ferritin is more dangerous than high cholesterol, high blood pressure, and diabetes.Heart disease is related to the amount of iron in the body,which, once absorbed, is rarely excreted other than by loss of blood.Excess iron in the body is stored in the form of ferritin,and excess iron stores increase the risk of heart disease.Iron deposits in cardiomyocytes and interstitial cells cause cell necrosis, loss of myocardial fibers, interstitial fibrosis, and focal calcification.Leading to atrioventricular enlargement, the inadequate blood supply to the myocardium, and involvement of the conduction system of the heart,resulting in myocardial contractile dysfunction.

Notably, Iron deficiency anemia heart disease patients themselves,in addition to the symptoms of anemia, but also with the progression of cardiac symptoms, manifested as compensatory myocardial contractility enhancement, palpitation, fatigue, heart shadow, and so on.Iron deficiency anemia heart disease patients themselves, in addition to the symptoms of anemia, but also with the progression of cardiac symptoms, manifested as compensatory myocardial contractility enhancement, palpitation, palpitation, fatigue, heart shadow,and so on.This is the heart disease caused by iron deficiency leading to anemia, and after the improvement of iron deficiency anemia, related heart disease symptoms can be improved.

Mechanism of Iron Deposition in Cardiac Dysfunction

Oxidative Stress and Lipid Metabolism

Iron deposition leads to an increase in free iron, as well as reactive oxygen species (ROS), which causes myocardial cell damage and antioxidant loss [32,33].The iron deposition also causes mitochondrial DNA damage, which affects cellular respiration and leads to heart muscle damage.Iron deposition can also lead to cardiac dysfunction by affecting lipid metabolism.Iron itself is a catalyst for lipid metabolism.It can produce peroxide free radicals that further attack the unsaturated fat chain in the cell membrane, which leads to lipid peroxidation.Moreover, low-density lipoprotein (LDL) can also be oxidized by ROS to oxidized LDL, which induces myocardial cell damage [34].The lipid peroxidation caused by iron deposition inhibits DNA damage repair, a process that further affects heart function.Kok et al.confirmed that the insulin resistance caused by iron overload can reduce the anti-lipolysis effect of insulin, reduce the body’s uptake of glucose, and increase the accumulation of lipid droplets in myocardial cells, all of which lead to myocardial dysfunction and myocardial injury [35].In iron deposition mouse models, amlodipine or verapamil can be used to treat iron deposition by blocking L-type calcium channels, which inhibit the accumulation of non-TF-bound iron in cardiomyocytes.Thus, oxidative stress and cardiac dysfunction can be alleviated [36].

Electrophysiological Change

Iron plays an important role in regulating cardiac electrophysiology.Iron deposition leads to a decrease in the amplitude of action potentials, a decrease in sodium current influx, and an increase in transient outward potassium current in cardiomyocytes.It also leads to cardiomyocyte necrosis, loss of myocardial fibers, interstitial fibrosis, and focal calcification.In the heart, the ferrous ion can enter cardiac myocytes through calcium channels to control their excitation and contraction.The increase in iron influx antagonizes calcium influx and leads to myocardial cell contraction disorder [37].Iron deposition can affect cardiac diastole and contraction and result in electrophysiological disorders.Schwartz et al.confirmed that iron deposition could lead to the apoptosis and fibrosis of myocardial cells and affect myocardial diastole and contraction [38].The oxidation of lipids and proteins leads to the enhancement of the activity of sodium-calcium ion exchangers, which results in myocardial systolic and diastolic abnormalities and arrhythmia.Laurita et al.found that cardiac electrophysiology is remarkably affected [39].Iron deposition mouse models present bradycardia and other phenotypes, indicating that iron overload leads to abnormal voltage-gated channels and arrhythmia symptoms.

Defects in Genes Associated with Iron Metabolism

A series of gene mutations involved in regulating iron metabolism often leads to iron metabolism disorder.The typical regulatory genes include the hepcidin antimicrobial peptide gene, which encodes hepcidin; the multiple regulation genes of hepcidin expression; and their downstreamFPNgenes.Abnormalities in hepcidin andFPNexpression can lead to hemochromatosis because of the iron deposition and organ damage caused by the intestinal intake of large amounts of iron [40].Hepcidin can be expressed in large quantities during the immune process and participate in immune response; thus,it can be used for thalassemia treatment.Hepcidin downregulation leads to iron deposition in the heart [41].Therefore, the use of its agonists has certain advantages in the treatment of iron deposition-related diseases.Small molecules, such as short peptide mimics or the adenine of hepcidin, can also improve the symptoms of iron deposition by reducing iron transport or upregulating hepcidin[41].Lipinski et al.found that in the process of piglet feeding, iron deficiency symptoms can be improved by dietary iron supplementation(0.1 and 0.4 g/kg),which leads to a sharp increase in serum hepcidin, inhibit intestinal iron absorption, reduce iron content in macrophages, and prevent iron absorption in the body [27].However, excessive dietary iron supplementation (4 and 10 g/kg) can seriously affect the daily gain of piglets and increase the lipid peroxidation levels in the duodenal mucosa and liver.

Oxidative stress refers to the balanced interaction between the production of reactive oxygen species (free radicals) and antioxidant defenses.If the body’s cells are chronically exposed to “oxidative stress,” it has been shown to be a key trigger for the development of diseases, particularly cancer, diabetes, atherosclerosis,neurodegenerative diseases (dementia), high blood pressure, stroke,and arthritis.The effect of oxidative stress on iron regulation is important.The increased reactive ROS in the intracellular environment will destroy the stability of iron-sulfur clusters and then lead to the degradation of IRBP.This phenomenon demonstrates an interaction between intracellular iron balance, metabolic activity, and ROS levels.Other studies have reported that elevated peroxide levels stimulate IRBP to bind to IRE located in ferritin mRNA, thereby altering mRNA stability and protein synthesis and translation.At the same time, iron-induced oxidative stress has an important impact on heart-related diseases.

Myocardial Cell Apoptosis and Fibrosis

Iron deposition considerably induces myocardial cell apoptosis.The tissue damage and cardiac dysfunction caused by iron deposition are also partially due to apoptosis activation.Wingman et al.selected 3-month-old gerbils to establish a model and divided the experimental gerbils into three groups [42].The control group was not given excessive iron; the iron deposition group was injected with iron dextran(0.1 g/kg) subcutaneously every five days; the iron-chelating agent treatment group was treated with the iron-chelating agent (0.1 g/kg) orally after iron overloading.After three months, compared with the control group, the expression of apoptosis-related markers remarkably increased in the cardiomyocytes of gerbils in the iron deposition group and remarkably decreased in the cardiomyocytes of

gerbils in the iron-chelating agent group.Two main signaling pathways are involved in iron deposition-induced cardiomyocyte apoptosis.The first is the PI3K/AKT signaling pathway, whose activation inhibits the apoptosis of myocardial cells and protects myocardial ischemia-reperfusion injury.This signaling pathway plays an important role in combating oxidative stress injury in cells [43].The other is the AKT/mTOR/p70S6K signaling pathway [44,45].In cardiomyocytes, mTOR is activated by Akt phosphorylation and further activates p70S6K phosphorylation, which inhibits cardiomyocyte apoptosis [46,47].This signaling pathway also plays an important role in cardiac iron deposition-induced myocardial apoptosis.The discontinuity of the myocardial membrane and the increase in the TDT-mediated dUTP-biotin nick end-labeling ratio can lead to DNA damage and cell membrane rupture, which results in myocardial fibrosis and cardiac dysfunction.Treatment with an iron-chelating agent can increase the integrity of the cell membrane and reduce myocardial apoptosis and fibrosis.

Ferroptosis

Ferroptosis is a kind of programmed cell death associated with the accumulation of iron-dependent lipid ROS and the consumption of plasma membrane polyunsaturated fatty acids, which involve lipid metabolism, amino acid metabolism, and iron metabolism.In detail,this process is induced by reduced glutathione (GSH, a scavenging compound)and(1S,3R)-RSL3(the inhibitor of glutathione peroxidase 4[GPX4])[48].GPX4 scavenges ROS and requires GSH as a substrate.The transmembrane transporter SLC7A11 and the transmembrane regulatory protein SLC3A2 form the glutamate/cysteine reverse transporter.When the inhibited of the reverse transporter leads to increased lipid ROS accumulation and subsequently cell death.Free iron ions in the cytoplasm are stored in ferritin to maintain iron homeostasis in the cell.Iron homeostasis is disrupted when ferritin expression is abnormal.Ferritin is selectively degraded by nuclear receptor co-activator 4 (NCOA4)-mediated by autophagy, resulting in increased intracellular free iron and iron death [49,50] (Figure 2).The main cause of iron deposition-related diseases is the production of a large number of ROS; recent studies have designed small molecular compounds that target ROS for targeted clearance.For example,in the mouse model, compounds, such as MitoQ, can take advantage of the characteristics of mitochondrial membrane voltage to carry antioxidants into the mitochondrial matrix to remove ROS, alleviate the symptoms of apoptosis, and avoid damage to mouse neurons and liver; thus, these compounds improve related functions [51].Ferroptosis-specific inhibitor, ferrostatin-1, can remarkably reduce Adriamycin-induced cardiotoxicity and improve the survival rate of experimental mice [52].Stamenkovic et al.found that ischemia-reperfusion injury can cause non-apoptotic cell death in the heart of adult rats, and the ferroptosis inhibitor FER-1 can also inhibit cell death [53].Gao et al.further proposed that transferrin and glutamine are inducers of ferroptosis in myocardial ischemia-reperfusion injury, and inhibition of glutamine decomposition can reduce myocardial injury caused by ischemia-reperfusion injury[54].

Figure 2 Occurrence and regulation of ferroptosis.Ferroptosis is induced by the cellular production of lipid ROS induced by GSH and (1S,3R)-RSL3.GPX4 scavenges ROS and requires GSH as a substrate.SLC7A11 and SLC3A2 form glutamate/cysteine reverse transporter.The inhibition of the reverse transporter leads to increased lipid ROS accumulation and cell death.Free iron ions in the cytoplasm are stored in ferritin to maintain iron homeostasis in the cell.Iron homeostasis is disrupted when ferritin expression is abnormal.Ferritin is selectively degraded by NCOA4-mediated autophagy, which results in increased intracellular free iron and iron-induced death.GPX4, glutathione peroxidase 4; ROS, oxygen species;GSH, glutathione; NCOA-4, nuclear receptor co-activator 4,TFR1, transferrin receptor 1.

Other Mechanisms

In a mouse ischemia-reperfusion model, transient ischemia-reperfusion can cause tissue damage and necrosis [55].The hearts of mice were cultured in vitro for ischemia-reperfusion and treated with the chelating agent deferoxamine at the beginning of perfusion.Compared with the control group, the heart function of mice in the deferoxamine group remarkably improved, and deferoxamine also regulated the release of lactate dehydrogenase during perfusion to inhibit heart injury [31].Therefore, inhibiting iron deposition has a remarkable protective effect on the ischemia-reperfusion injury of the heart.Kobayashi et al.found substantially increased iron and TF receptor contents in myocardial cells,which suggests that iron plays an important role in myocardial ischemia-reperfusion [56].Anthracycline antitumor drugs have remarkable cardiotoxicity, which may be caused by mitochondria damage and oxidative stress induced by iron deposition [57, 58].Moreover, transfusion therapies for sickle anemia and other diseases also lead to excessive iron intake because iron is utilized by macrophages and is difficult to expel from the body effectively.In this case, cardiac iron deposition is highly remarkable and further leads to abnormal cardiac function [59].

Iron Removal Treatment Can Effectively Prevent and Control Heart Disease

According to current clinical practice and experimental research,effective iron removal treatment can relieve iron deposition in the body and substantially improve the treatment and prognosis of heart-related diseases.Iron chelation therapy is a better option for cardiac patients who do not tolerate traditional bloodletting.Iron chelators neutralize excess unbound iron ions in the body and prevent iron deposition.The most commonly used iron chelators are deferoxamine, deferiprone, dexrazoxane, and deferasirox.As the most widely used iron-chelating agent, deferoxamine can considerably reduce the heart iron level in patients with severe thalassemia and other iron overload diseases and improve cardiac function [25–60].Deferoxamine has a remarkable curative effect in the treatment of cardiovascular diseases.Kumar et al.proved that deferoxamine can effectively reduce ROS in the mitochondria of rat cardiomyocytes and improve vasodilation in patients with coronary artery disease [30].Deferiprone has a relatively small molecular weight and can easily enter muscle cells and organelles, such as lysosomes and mitochondria.The combined treatment of deferiprone and deferoxamine has advantages in removing iron overload in the heart and liver [61].Dexrazoxane, as the drug approved by the FDA, can inhibition of ferroptosis by ferrostatin-1 and significantly reduce doxorubicin-induced cardiotoxicity in cancer patients [62].Dexrazoxane is a chelating agent that can penetrate the mitochondria.Dexrazoxane had a remarkable effect on treating rat heart ischemia-reperfusion injury in the rat model but had little effect on the pig model.Deferasirox can effectively reduce iron content in heart disease associated with iron overload [61].Although the effect of iron chelating agents has been widely recognized in clinical practice, these agents still have some toxic side effects.Researchers can combine the advantages of existing chelating agents with other therapies to develop a more efficient iron removal treatment for the diseases caused by iron deposition in the future.

Conclusion

Iron is an essential trace element in all living things.It participates in many important physiological processes such as cell proliferation and differentiation, electron transfer, cellular respiration, energy metabolism, and detoxification.It regulates the expression of nitric oxide synthase, PKC-β,p21,and other genes through a catalytic redox reaction.The role of iron overload in heart disease has recently attracted increasing attention.Some proteins are involved in cardiac iron metabolism,and their functions and regulation play an important role in cardiac diseases, such as myocardial ischemia-reperfusion and β-thalassemia.

A series of changes in myocardial cells induced by iron deficiency would affect the structure and function of the heart.Iron deposition can cause myocardial cell damage, affect myocardial diastole and contraction, leading to electrophysiological disorder, and even induce myocardial cell apoptosis.Although abnormal iron content and disturbance of iron metabolism in animals are closely related to the occurrence and development of heart-related diseases, the specific pathogenesis remains to be elucidated.At present, iron supplementation can be used to improve the heart failure caused by iron deficiency in patients, but the fatality rate has not been effectively improved.Iron removal can also prevent and control heart diseases,but the iron chelating agent's toxicity and side effects limit its wide use.Simple therapy can no longer meet clinical needs.

In fact, many studies have clinically demonstrated an association between iron metabolism and heart-related diseases, such as myocardial hypertrophy, dilated cardiomyopathy, and heart failure.These studies elucidated the influence of iron metabolism on the pathogenesis and progression of heart-related diseases from different perspectives and mechanisms.They confirmed that several iron-related proteins and drugs could be used as therapeutic targets or for treating heart-related diseases.

The processes of iron accumulation and iron death occurred mainly in the mitochondria of cardiomyocytes after doxorubicin treatment.In addition, the administration of iron death inhibitors can also significantly reduce the heart injury caused by ischemia-reperfusion,which provides a very promising new idea and strategy for the prevention and treatment of clinical myocardial infarction and other cardiac diseases.

Notably, too much iron in the heart can also trigger a surge in free radical production, leading to cell damage.Therefore, the human body has a strict regulation mechanism of iron metabolism to maintain the balance between iron absorption and demand.Intervention for iron metabolism disorder may play an important role in alleviating oxidative stress in the heart and other organs and can be further used to treat heart-related diseases.Interventions targeting iron metabolism should also be combined with other treatments to facilitate the recovery of heart function.Elucidating the precise molecular mechanism of cardiac diseases caused by iron abnormality and conducting experimental animal model studies are necessary to develop new therapeutic methods in the future.