Biochimica et Biophysica Acta (BBA) - General Subjects
ReviewIron in arterial plaque: A modifiable risk factor for atherosclerosis
Introduction
Nearly three decades ago, it was suggested that a state of sustained iron depletion or mild iron deficiency exert a primary protective action against ischemic heart disease [1], [2], [3], [4], [5], [6], [7], [8]. This “iron hypothesis” was offered as an explanation of the sex difference in coronary disease incidence and the increase in incidence among women after menopause. Despite significant controversy, the idea has achieved standing as a plausible and testable hypothesis [9], [10], [11], [12], [13]. A protective effect of iron depletion that may have multiple beneficial consequences is decreased availability of redox-active iron in vivo [2], [14].
It has been proposed that the amount of free iron available at sites of oxidative or inflammatory injury is a function of the stored iron level and that the availability of redox-active iron in vivo approaches its minimum in the state of iron depletion. There is significant experimental support for this concept [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35]. In particular, it has been shown that removal of stored iron from the body can decrease the amount of iron deposition within atherosclerotic lesions in animal studies. Depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size in these studies and increases plaque stability [18], [31], [36], [37], [38]. The original formulation of the iron hypothesis did not specify a mechanism. There may well be multiple mechanisms by which iron depletion protects against heart disease. This animal work as well as a number of more recent studies focuses attention on pathogenic roles for iron within arterial plaque. Iron is present in atherosclerotic plaque at concentrations that appreciably exceed that found in healthy arterial tissue. This iron is not simply an inert component of plaque. Some of the arterial iron is redox active and the ferritin- and hemosiderin-bound iron compartment remains a reservoir of potentially reactive iron within lesions. Does this iron have a role in the production of clinical events? Does it affect plaque stability? Are there any modalities that can decrease the concentration of plaque iron? Would such removal of plaque iron by induced iron deficiency or treatment with iron chelators decrease plaque vulnerability? There have now been a number of studies that provide evidence for one potential mechanism by which iron depletion may protect against atherothrombotic disease. This article will review that work and its relevance to the iron hypothesis.
Section snippets
Presence and modifiability of plaque iron: Early work in animal models and in human studies
In a 1992 study, Smith et al. [39] demonstrated the presence of catalytic iron in material taken from human atherosclerotic lesions, providing important indirect support for the iron hypothesis. Iron deposits in atherosclerotic lesions in the cholesterol-fed rabbit were later confirmed by nuclear microscopy and in human lesions by conventional histologic staining [38], [40].
Matthews et al. [41] observed a large and significant decrease in total aorta cholesterol concentration after iron
Iron in human carotid lesions
Using electron paramagnetic resonance (EPR) spectroscopy and inductively coupled plasma mass spectroscopy (ICPMS) Davies and colleagues [46] quantified iron in ex vivo carotid lesions and in healthy human arteries. They found elevated levels of iron in the intima of lesions compared with healthy controls (0.370 versus 0.022 nmol/mg tissue by EPR, 0.525 versus 0.168 nmol/mg tissue by ICPMS, P p < 0.05 in both cases). Cholesterol levels in lesions correlated positively with iron accumulation. In
Angiotensin II and arterial iron deposition
Ishizaka et al. [57] found that angiotensin II infusion for 7 days in rats caused a > 20-fold increase in ferritin protein expression over control values in aortic endothelial and adventitial cells, including monocytes/macrophages. Stainable iron was seen in the adventitial layer of aorta from angiotensin II infused animals. Iron chelation suppressed aortic induction of ferritin and heme oxygenase-1 (HO1) and suppressed upregulation of mRNA levels of monocyte chemoattractant protein-1 (MCP1). In
Haptoglobin polymorphisms and plaque iron content
Asleh et al. [59] suggested that hemoglobin within plaque derived from microvascular hemorrhage is cleared more slowly from plaques associated with haptoglobin (Hp) 2-2 genotype as compared to Hp 1-1 plaques. The Hp 2-2 genotype is associated with an increased risk of atherosclerotic cardiovascular disease. These investigators then created a type 2 Hp allele in the apoE-deficient mouse and explored the effect of Hp 2-2 genotype on iron, lipid peroxidation and macrophage accumulation in plaque.
Heme oxygenase-1 polymorphisms and plaque iron
A similar pattern may occur with promoter polymorphisms in HO1, an inducible enzyme that catalyzes the rate limiting step in heme catabolism. Heme catabolism is a key function in mobilizing macrophage iron derived from ingested erythrocytes. Alterations in the activity of HO1 influence the rate of clearance of hemoglobin-derived iron from macrophages. In the HO1 deficient mouse (HO1−/−) conspicuous iron loading is seen in Kupffer cells, hepatocytes, hepatic vascular tissue, and renal cortical
Quantitation of carotid plaque iron by MRI based T2⁎ measurement
Raman et al. [68] investigated the role of iron deposition in carotid plaque instability using a novel approach of in vivo plaque characterization by a noninvasive, noncontrast magnetic resonance based T2⁎ measurement. The method was validated using ex vivo plaque analyses of intra-plaque iron composition. Symptomatic patients had significantly shorter plaque T2⁎ values (20.0 ± 1.8 ms) compared with asymptomatic patients (34.4 ± 2.7 ms, p < 0.001), respectively, which is consistent with a shift in
Inflammation, IL-6, hepcidin and iron in arterial plaque
Hepcidin level is a major determinant of the amount of iron retained within macrophages [69], [70], [71], [72]. Production of hepcidin is regulated by a number of interrelated factors. Elevated levels, which favor macrophage iron retention, are encountered with increased iron intake, infection and inflammation. Reduced hepcidin levels are associated with iron deficiency, hypoxia, anemia and homozygous hemochromatosis. Interleukin 6 (IL-6) upregulation as seen in inflammatory states induces
Genetic hemochromatosis and defective iron retention in the macrophage
Genetic hemochromatosis is another factor that could strongly influence the iron concentration of arterial plaque. Because HFE mutations are almost always associated with very low hepcidin concentrations and consequently with decreased retention of iron by the macrophage [71], [72], it appears likely that these mutations may, counter-intuitively, cause more rapid clearance of iron from arterial lesions. The classic finding in inherited hemochromatosis is misplaced hepatic iron. The disease is
The FeAST trial
Findings of a first randomized trial of mild iron reduction therapy in elderly patients with established peripheral vascular disease (the “FeAST” trial) have been recently reported [9], [76], [77]. The trial assessed the potential benefit of mild iron reduction therapy in secondary prevention of cardiovascular disease. It was therefore not a fully valid test of primary prevention as postulated by the iron hypothesis. No overall statistically significant cardiovascular benefit was found.
Iron in arterial plaque: A modifiable risk factor for atherosclerosis
These findings from animal models of atherosclerosis and from studies of human atherosclerotic plaque provide support for the concept that elevated arterial iron levels play a significant role in the pathogenesis of atherosclerosis. Both the animal studies and long clinical experience with the effects of iron deficiency anemia on storage iron show that iron in arterial plaque can be mobilized for erythropoiesis and thereby reduced in concentration. It should be feasible to achieve the normally
Concluding comment: Is stored iron safe?
Suggesting that one disorder, i.e. atherosclerotic plaque, might be treatable by the induction of a second disorder, i.e. iron depletion, may be seen as a controversial proposal largely because there is a deeply held and widely prevalent assumption that iron in storage is inherently safe. The assumption is based ultimately on decades old traditional medical practices rather than on appropriately designed rigorous clinical trials. It has been previously noted [14] that “A benefit of iron
References (91)
Iron and the sex difference in heart disease risk
Lancet
(1981)The iron paradigm of ischemic heart disease
Am. Heart J.
(1989)Stored iron and myocardial perfusion deficits
Am. Heart J.
(2002)Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis
Am. Heart J.
(2003)Is stored iron safe?
J. Lab. Clin. Med.
(2004)- et al.
Nutritional iron restriction diminishes acute complement-dependent lung injury
Nutr. Res.
(1989) - et al.
Iron-deficient mice fail to develop autoimmune encephalomyelitis
J. Nutr.
(2003) - et al.
Serum aminotransferase levels as an indicator of the effectiveness of venesection for chronic hepatitis C
J. Hepatol.
(1995) - et al.
Role of dietary iron restriction in a mouse model of Parkinson's disease
Exp. Neurol.
(2004) - et al.
The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion
FEBS Lett.
(1999)
Restored vulnerability of cultured endothelial cells to high glucose by iron replenishment
Biochem. Biophys. Res. Commun.
Beneficial effects of blood donation on high density lipoprotein concentration and the oxidative potential of low density lipoprotein
Atherosclerosis
The iron chelator desferrioxamine inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit
Free Radic. Biol. Med.
A nuclear microscopy study of trace elements Ca, Fe, Zn and Cu in atherosclerosis
Nucl. instrum. methods phys. res., B Beam interact. mater. atoms
Iron and atherosclerosis: inhibition by the iron chelator deferiprone (L1)
J. Surg. Res.
Correlation of iron and zinc levels with lesion depth in newly formed atherosclerotic lesions
Free. Radic. Biol. Med.
Concentrations of iron correlate with the extent of protein, but not lipid, oxidation in advanced human atherosclerotic lesions
Free Radic. Biol. Med.
Association of body iron stores with low molecular weight iron and oxidant damage of human atherosclerotic plaques
Free Radic. Biol. Med.
Iron in human atheroma and LDL oxidation by macrophages following erythrophagocytosis
Atherosclerosis
Foam cell death induced by 7[beta]-hydroxycholesterol is mediated by labile iron-driven oxidative injury: Mechanisms underlying induction of ferritin in human atheroma
Free Radic. Biol. Med.
HMG-CoA reductase inhibitors upregulate heme oxygenase-1 expression in murine RAW264.7 macrophages via ERK, p38 MAPK and protein kinase G pathways
Cell. Signal.
Statin-mediated cytoprotection of human vascular endothelial cells: a role for Kruppel-like factor 2-dependent induction of heme oxygenase-1
J. Thromb. Haemostasis
In vivo atherosclerotic plaque characterization using magnetic susceptibility distinguishes symptom-producing plaques
J. Am. Coll. Cardiol. Img.
Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS
Blood
Novel urine hepcidin assay by mass spectrometry
Blood
Iron as the malignant spirit in successful ageing
Ageing Res Rev.
Inhibition of iron absorption prolongs the life span of Drosophila
Mech. Ageing Dev.
Stored iron and ischemic heart disease. Empirical support for a new paradigm
Circulation
Stored iron and vascular reactivity
Arterioscler Thromb. Vasc. Biol.
Macrophage iron, hepcidin, and atherosclerotic plaque stability
Exp. Biol. Med.
Over-expression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques
Exp. Biol. Med.
The iron-heart hypothesis: search for the ironclad evidence
JAMA
Can iron chelators influence the progression of atherosclerosis?
Hemoglobin
The iron hypothesis of atherosclerosis and its clinical impact
Ann. Med.
Iron and thrombosis
Ann. Hematol.
Iron stores and vascular function in voluntary blood donors
Arterioscler. Thromb. Vasc. Biol.
Iron depletion decreases lung injury after systemic complement activation
Fed. Proc.
Effects of iron deprivation or chelation on DNA damage in experimental colitis
Int. J. Colorectal. Dis.
Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice
Circulation
Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients
Ann. N. Y. Acad. Sci.
A low-iron-available, polyphenol-enriched, carbohydrate-restricted diet to slow progression of diabetic nephropathy
Diabetes
Near-iron deficiency-induced remission of gouty arthritis
Rheumatology (Oxford)
Depletion of iron and ascorbate in rodents diminishes lung injury after silica
Exp. Lung. Res.
Long-term phlebotomy with low-iron diet therapy lowers risk of development of hepatocellular carcinoma from chronic hepatitis C
J. Gastroenterol.
Dietary iron restriction increases plaque stability in apolipoprotein-e-deficient mice
J. Biomed. Sci.
Cited by (149)
Iron and atherosclerosis: Lessons learned from rabbits relevant to human disease
2023, Free Radical Biology and MedicineIron metabolism and atherosclerosis
2023, Trends in Endocrinology and MetabolismIron overload, oxidative stress and vascular dysfunction: Evidences from clinical studies and animal models
2022, Biochimica et Biophysica Acta - General SubjectsCitation Excerpt :Reinforcing, controlled studies with animal models using transgenic mice or parenteral/oral iron administration also reported a causative role for iron on these cardiovascular risk factors such as dyslipidemia and elevated lipid peroxidation, highlighting the oxidative stress as the underlying mechanism [62–64]. Finally, numerous clinical studies indicated that the endothelial dysfunction, a common pathway for those aforementioned conditions, is also present in iron overload [65–67] and evidences from basic and clinical researches have suggested a potential role for these iron-induced damages for vasculopathy-associated myocardial infarction (MI), atherosclerosis and stroke [52,68,69]. The term “iron hypothesis” was coined by Jerome Sullivan, in 1981, proposing that iron overload potentially induces cardiovascular injury, and its depletion should promote cardiovascular protection.
NOD1 splenic activation confers ferroptosis protection and reduces macrophage recruitment under pro-atherogenic conditions
2022, Biomedicine and PharmacotherapyCitation Excerpt :However, connections between iron metabolism, ferroptosis, specific leukocyte subset mobilizations and clinical data remain poorly defined. In addition, there are strong connections between iron homeostasis and cardiovascular diseases such as atherosclerosis [3,16–19]. Inflammation and oxidation are prominent mechanisms contributing to the complex process of atherogenesis, and iron leads to enhanced free radical production and ferroptosis [16,20].
Effects of radiation on endothelial barrier and vascular integrity
2021, Tissue Barriers in Disease, Injury and RegenerationInhibition of ferroptosis alleviates atherosclerosis through attenuating lipid peroxidation and endothelial dysfunction in mouse aortic endothelial cell
2020, Free Radical Biology and Medicine