Role of Iron in the Development of Atherosclerosis

It is often presented that people need to increase their iron intake by consuming more red meat or green vegetables to prevent anaemia and other diseases linked to low iron. Anaemia is a condition where the body does not make enough healthy red blood cells preventing the body’s tissues from getting sufficient oxygen. There is no doubt that iron is a vital element needed for various processes within our body; however, it is important to know that too much iron is toxic and can be equally as harmful, if not more. The purpose of this dissertation is to show the importance of iron levels in maintaining a healthy body, focussing on the function of the heart. It aims to show that it is crucial for iron levels to be tightly regulated and what problems can arise when iron levels drop below or exceed the normal level. Heart disease such as atherosclerosis, the narrowing of the arteries, will be discussed.

Scientific Abstract

Iron is one of the most essential elements in the body and is vital in many biological processes; however, when iron levels drop below or exceed the normal level, it can have detrimental effects on the organs in the human body, especially the heart which is the focus of this dissertation. Many studies have investigated the role of iron in different heart diseases, but the link is not yet fully understood. This dissertation aimed to show the importance of maintaining iron at the correct level in the body and the consequences which occur when they are not. Iron overload can lead to the oxidation of low-density lipoproteins which play a role in the development of atherosclerotic plaques. Additionally, high iron levels can affect the function of calcium channels in the heart, this is seen in cardiomyopathy. On the other hand, iron deficiency leads to ineffective erythropoiesis causing the heart to work harder resulting in physical changes in the heart as seen in heart failure.

This dissertation discusses the roles of iron, metabolism and looks at studies that have helped develop our understanding of the relationship between iron and heart diseases which arise when levels are not maintained.

Definition of What Is Iron

Iron is one of the most essential minerals in the body. It is a transition metal that can accept and donate electrons in oxidation-reduction reactions. These reactions are vital for numerous processes in the body. There are two main types of iron; ferrous iron and ferric iron. Ferric iron, Fe3+, is insoluble and is found in green vegetables, whereas ferrous iron, Fe2+, is soluble and is found in red meats and fish. Due to ferrous iron being soluble, it can be absorbed more efficiently than ferric iron.

Iron Absorption, Transport, and Storage

On average, a person will consume 10 to 20 mg of iron daily, however, only 5 to 35% will be absorbed depending on the individual’s requirements (Abbaspour et al., 2014). Normally, a male adult will have around 35 to 45 mg of iron per kilogram, whereas a premenopausal women’s iron levels will be lower due to menstruation. There is a steady loss of iron by desquamation of skin, sloughing of intestinal cells and blood loss which is balanced by steady absorption and recycling. Iron absorption takes place in the small intestine, in the duodenum and part of the upper jejunum. For iron to be absorbed, it needs to be converted from ferric iron into ferrous iron. This is done by a ferric reductase enzyme known as duodenal cytochrome B. The low pH in the duodenum aids this reduction. Ferrous iron is then transported from the lumen of the duodenum into the enterocyte by the divalent metal transporter (DMT-1). When the iron is in the enterocyte, it can either be stored as ferritin or transported across the basal membrane into the plasma through a transmembrane protein, ferroportin-1. For iron in the plasma to be transported around the body, iron is converted back into ferric iron by two copper-containing enzymes. Ceruloplasmin is an enzyme found in the plasma, and hephaestin is located on the basolateral membrane of the enterocyte (Ems, 2019). Ferric iron can then be transported around the body attached to transferrin. Due to the body having no mechanisms for iron loss, iron levels are maintained by tightly regulating absorption (Wallace, 2016). This is done by an important regulatory hormone called hepcidin which works by inhibiting efflux through ferroportin by binding to or degrading it (Nemeth and Ganz, 2006).

Plasma transferrin is an iron-binding glycoprotein that contains two sites which can bind ferric iron tightly but reversibly. Transferrin transports iron around the body to any cell which contains the transferrin receptor protein 1 (TfR1) (Gkouvatsos et al., 2012). Transferrin is endocytosed by cells containing the clathrin-dependant receptor, then once inside, the iron is released. There are four transferrin species that have different iron affinities and distribute iron to various parts of the body. Diferric transferrin is thought to be the most abundant form of transferrin as it has the highest affinity for TfR1 and it is believed that this form of transferrin delivers iron to the erythrocytes (Finberg, 2019).

Iron is distributed around the body for different purposes; approximately 70% of iron is found in haemoglobin (Hb) in red blood cells (RBCs) and in myoglobin which is found in muscle cells. 5% of iron is used in haem-containing enzymes and proteins (Johnson-Wimbley and Graham, 2011), and the remaining 25% of iron can be stored as ferritin or hemosiderin which is found in the liver, spleen, bone marrow and other areas (Saito, 2014). Ferritin is the major form of iron storage. It is a globular protein arranged into a hollow shell where up to 4500 iron atoms can be packed in. There are pores on its surface which allow the iron to enter and exit regulating iron levels (Hahn et al., 1943). However, when ferritin levels are exceeded, iron can be stored in hemosiderin. Hemosiderin has no fixed composition, consisting of ferritin particles, denatured proteins, and lipids. It is normally found in macrophages, glial cells and other cells of the reticuloendothelial system. When iron levels increase further, excess hemosiderin is deposited in the liver and heart (Fischbach et al., 1971).

Consequences of Iron Overload or Deficiency

Iron deficiency (ID) can lead to anaemia and according to the World Health Organisation, it affects around one-quarter of the world’s population. ID is most common in premenopausal women due to loss of iron through heavy menstruation or due to pregnancy. But, ID can be caused by other things too such as poor diet or mutations in genes for iron absorption such as the DMT-1 protein or the transferrin receptor (Dev and Babitt, 2017). Reduced iron levels can lead to minor symptoms such as fatigue and headache; however, it is also known to cause more severe problems such as impaired cognitive development and heart failure (Jáuregui-Lobera, 2014).

On the other hand, iron overload can cause just as many problems. Iron overload can be due to hereditary haemochromatosis (mutations in the hepcidin gene), thalassemia’s (abnormalities in globin synthesis), or transfusion overload (due to many blood transfusions). In iron overload, the transferrin levels are exceeded, and so non-transferrin bound iron (NTBI) is taken up by different organs. The excess iron leads to oxidative damage and increases the risk of liver failure, heart attack and heart failure along with other endocrine diseases. Iron overload has also been linked to neurodegenerative diseases such as Alzheimer’s and Parkinson’s (Dev and Babitt, 2017).

Roles of Iron

Iron has many different roles in the body. A major role of iron is in the transport of oxygen around the body (Wallace, 2016). Iron makes up a vital component in the erythrocytes called haemoglobin. Iron is the central atom in the haem group. It allows oxygen to bind reversibly and be transported around the body to active cells; therefore, it is essential that iron is incorporated into erythrocytes and so erythropoiesis has a high iron demand. The heart is a muscle that requires a large amount of energy and struggles when iron levels are low (Fitzsimons and Doughty, 2015). When iron levels drop below normal, it affects RBC production and so the heart needs to work harder to supply the body with oxygenated blood. This often leads to heart palpitations.

Additionally, iron is a redox element present in some enzymes in metabolic pathways where the enzymes act as electron carriers. For example, in oxidative metabolism, iron’s role is to transfer energy to the mitochondria. There are other iron-containing enzymes too which play a role in the synthesis of steroid hormones, bile acids and controlling some neurotransmitters in the brain.

Another area where iron is important is in DNA metabolism as many DNA repair enzymes, such as helicase and nucleases, use iron as a cofactor to function (Puig et al., 2017).

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Over the last few decades, studies have found iron to have a role in the development of the immune system where iron is necessary for the proliferation and maturation of immune cells (Soyano and Gomez, 1999). More recently, it has been found that iron is also important in ferroptosis which is an iron-dependant and reactive oxygen species (ROS)-reliant form of cell death (Kobayashi et al., 2018) which plays an important regulatory role in the development of diseases (Li et al., 2020). Ferroptosis is biochemically different from other forms of cell death; it is initiated by the failure of antioxidant defences resulting in the oxidative degeneration of lipids leading to cell death.

Iron Overload

Iron overload can occur in patients who already have genetic and acquired blood disorders such as beta-thalassemia major and sickle cell disease. These diseases can cause ineffective erythropoiesis and so the patients depend upon regular RBC transfusions which can lead to iron overload. But overload can also be due to diet and iron accumulating over many years. Iron overload can cause iron to accumulate in the organs; however, iron accumulation in the heart can be particularly dangerous.

In 1981, it was proposed by Sullivan that increased iron stores were a risk factor for cardiovascular disease. He proposed that cardiovascular disease (CVD) cases in premenopausal women are lower in comparison to men due to women having lower iron stores (iron lost through menstruation). He believed that ID could protect against CVD and a way to prevent CVD was by regular venesection (Sullivan, 1981). Since Sullivan’s hypothesis, many studies have been conducted testing his theory. Currently, there are more studies that agree and support the iron hypothesis; nevertheless, there are also several experiments that either contradict Sullivan’s theory or did not find any evidence to linking iron to CVD.

Atherosclerosis

Atherosclerosis is a disease where a plaque builds up inside an artery. The plaque can be composed of fat, cholesterol, calcium or other components of the blood. Over time, these build up and harden leading to the narrowing of the artery. The lumen becomes narrower and so blood flow becomes restricted. If left untreated, the plaque can completely block blood flow and prevent the delivery of oxygen to respiring cells and tissues. This can lead to ischemia, if the blockage is in an artery in the heart, it can lead to a heart attack or if it blocks a vessel that supplies the brain, a stroke can occur (Rafieian-Kopaei et al., 2014).

The role of iron in the development of atherosclerosis is not yet fully understood and there are some studies that support the role of iron overload in atherosclerosis, but there are also studies which contradict these findings.

Studies linking iron overload to atherosclerosis believe iron takes part in the redox reactions. Iron changes from the ferrous state into the ferric state transferring an electron to form highly reactive oxygen species (ROS) such as the hydroxyl radical during mitochondrial electron transport. This redox reaction on iron is known as the Fenton reaction.

If there are large amounts of iron in the tissues, it can catalyse the formation of oxygen free radicals. These unstable radicals cause the oxidation of low-density lipoproteins. Oxidised low-density lipoproteins (oxLDL) promote the activation of endothelial cells which produce adhesion molecules and chemoattractants which attract monocytes and lymphocytes to the arterial wall (Linton et al., 2000). Macrophages endocytose oxLDLs resulting in the formation of foam cells which over time will develop into atherosclerosis. Foam cells are a type of macrophage that migrate to fatty deposits on arterial walls where they ingest more LDLs and become full of lipids giving then a foam-like appearance. Foam cells accumulate as the oxLDLs previously ingested increases macrophage’s uptake of oxLDLs by causing more scavenger receptors to be expressed on the cells surface (Sharkey-Toppen et al., 2014).

Experiments have been conducted to support this hypothesis. 26 rabbits were separated into four different groups; iron-overload/hypercholesterolemic (using intramuscular injections of iron), iron-overloaded, hypercholesterolemic (rabbit food enriched with 0.5% cholesterol) and an untreated group. Serum iron and ferritin levels were measured throughout the study and they found that in iron-overload/hypercholesterolemic and hypercholesterolemic groups, the aortas of these rabbits were narrowed but the iron-overload/hypercholesterolemic had the greatest narrowing of the aorta. The results they found agreed with there being a positive correlation between iron and atherosclerosis.

However, there are limitations to this experiment as it was conducted on an animal model, a rabbit, and so cannot say with certainty that the same results will occur in humans. Additionally, the rabbits were artificially iron-overloaded, this is different from how iron-overload would occur in real life. Therefore, more studies are needed to prove the relationship between the overload of iron stores and atherosclerosis in humans (Araujo et al., 1995).

A study from 2012 also supports iron overload leading to atherosclerosis. In this experiment, increased iron storage was linked to increased oxidative stress, inflammation, and carotid intima-media thickness. The study was conducted on 72 healthy men and was able to clearly show an association between body iron stores with atherosclerosis. Even though this study showed a positive correlation, there are some limitations, one being that a relatively small sample size was used and so the results are not representative of a larger population and so further experiments need to be done (Syrovatka et al., 2011).

However, a study conducted in 2001 contradicts these findings. They reported that atherosclerotic lesions were reduced in apolipoprotein E-deficient (apoE-deficient) mice that were fed high-iron diets. Their results showed that in this group of mice, the aortic lesions were significantly reduced compared to mice who were fed the low-iron diet. Additionally, the results suggest that as iron levels increased, the rate of lesion development decreased. The reasoning behind these findings is unknown, but the researchers believe in several possible mechanisms. One theory is that iron controls gene expression for the scavenger proteins mentioned earlier, or even for adhesion molecules on the artery wall. Another idea, is that bioactive molecules, which are involved in the formation of atherosclerotic plaques, are destroyed by the iron meaning lesion formation is decreased (Kirk et al., 2001).

The findings from the 2001 study are the opposite of the findings from other studies. This may be due to different models being used, different environmental conditions, research methods and the pre-existing condition of the model being used. All these factors contribute to the different results seen in the studies.

Coclusion

Even though more studies are needed to support the role of iron in the pathogenesis of atherosclerotic plaques, it seems likely that iron does play an important role in their formation, alongside other risk factors such as hypertension, obesity, diabetes and more. It is suggested that iron regulates the oxidative modification of lipoproteins and impacts the initiation, progression and the destabilisation of the plaque (Kraml, 2017).