Intraplaque iron as a modifiable atherogenic factor.
Jerome Sullivan, University of Central Florida College of Medicine
1 July 2009
Comment on: Tavora F, et al. BMC Cardiovascular Disorders 2009; 9(1):27.
The significance of the findings of Tavora et al (1) on iron and myeloperoxidase in unstable atherosclerotic plaques is best appreciated in the context of the growing literature on the role of iron as a modifiable risk factor for atherosclerosis (2). The study also provides evidence compatible with the "iron/heart hypothesis" that postulates a protective effect of iron depletion against cardiovascular disease (3-5).
Significant increases in iron concentration are present in human atherosclerotic lesions and in lesions in cholesterol fed animals in comparison to levels in the healthy arterial wall (6-8). Iron concentration (7) and induction of ferritin expression (9) are increased in very early lesions in cholesterol fed rabbits. Systemic iron reduction can decrease the intraplaque concentration of iron (10). In recent animal studies, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability (10-12).
A study of ex vivo human carotid atherosclerotic lesions found transferrin receptor 1 (TfR1) expression positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L and ferritin expression (13). Highly expressed TfR1 and ferritin in CD68 positive macrophages were significantly associated with development and severity of human carotid plaques. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma.
Several factors associated with increased arterial disease or increased cardiovascular events are also associated with increased plaque iron. Infusion of angiotensin II in rats increases ferritin levels and arterial thickness (14). These changes are reversed by treatment with the iron chelator deferoxamine. A human polymorphism for haptoglobin associated with increased cardiovascular disease is characterized by increased lesional iron (15). Heme oxygenase 1 (HO1) is a key component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms associated with weaker upregulation of the enzyme are associated with increased cardiovascular disease (16;17). The hormone hepcidin promotes retention of iron within macrophages and is upregulated by inflammation-induced synthesis of IL-6. The association of cardiovascular disease with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages (2).
Iron depletion has been proposed as a protective factor against cardiovascular disease. Increasing evidence suggests that an important mechanism for this protection involves a reduction in iron levels within atherosclerotic plaque. Diminished hepcidin levels and defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload (18). Protection against atherosclerotic lesions in hemochromatosis has been reported (19).
Tavora et al (1) suggest that the molecular relationship between iron and myeloperoxidase is unknown although they recognize that myeloperoxidase contains iron. It appears possible that myeloperoxidase activity is decreased in iron deficiency (20-22). Iron could be a limiting factor for myeloperoxidase formation at very low iron levels. Diminished inflammatory injury in association with reduction in myeloperoxidase activity by induced iron deficiency was first reported 20 years ago (20). Myeloperoxidase is thus a potentially modifiable coronary risk factor. Future studies are needed to determine if induced depletion of plaque iron can also lower intraplaque myeloperoxidase levels.
Jerome L. Sullivan, MD, PhD University of Central Florida College of Medicine jlsullivan3@gmail.com
(1) Tavora F, Ripple M, Li L, Burke A. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovascular Disorders 2009; 9(1):27. (2) Sullivan JL. Iron in arterial plaque: A modifiable risk factor for atherosclerosis. Biochim Biophys Acta - General Subjects 2009; 1790(7):718-723. (3) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981; 1(8233):1293-1294. (4) Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J 1989; 117(5):1177-1188. (5) Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003; 145(2):190-194. (6) Stadler N, Lindner RA, Davies MJ. Direct Detection and Quantification of Transition Metal Ions in Human Atherosclerotic Plaques: Evidence for the Presence of Elevated Levels of Iron and Copper. Arterioscler Thromb Vasc Biol 2004; 24(5):949-954. (7) Ponraj D, Makjanic J, Thong PS, Tan BK, Watt F. The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion. FEBS Lett 1999; 459(2):218-222. (8) Raman SV, Winner MW, III, Tran T, Velayutham M, Simonetti OP, Baker PB et al. In Vivo Atherosclerotic Plaque Characterization Using Magnetic Susceptibility Distinguishes Symptom-Producing Plaques. J Am Coll Cardiol Img 2008; 1(1):49-57. (9) Pang JH, Jiang MJ, Chen YL, Wang FW, Wang DL, Chu SH et al. Increased ferritin gene expression in atherosclerotic lesions. J Clin Invest 1996; 97(10):2204-2212. (10) Minqin R, Rajendran R, Pan N, Kwong-Huat TB, Ong WY, Watt F et al. The iron chelator desferrioxamine inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit. Free Radic Biol Med 2005; 38(9):1206-1211. (11) Lee TS, Shiao MS, Pan CC, Chau LY. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation 1999; 99(9):1222-1229. (12) Lee HT, Chiu LL, Lee TS, Tsai HL, Chau LY. Dietary iron restriction increases plaque stability in apolipoprotein-e-deficient mice. J Biomed Sci 2003; 10(5):510-517. (13) Li W, Xu LH, Forssell C, Sullivan JL, Yuan XM. Overexpression of Transferrin Receptor and Ferritin Related to Clinical Symptoms and Destabilization of Human Carotid Plaques. Exp Biol Med 2008; 233(7):818-826. (14) Ishizaka N, Saito K, Mori I, Matsuzaki G, Ohno M, Nagai R. Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II-Infused Rats. Arterioscler Thromb Vasc Biol 2005; 25(11):2282-2288. (15) Asleh R, Guetta J, Kalet-Litman S, Miller-Lotan R, Levy AP. Haptoglobin Genotype- and Diabetes-Dependent Differences in Iron-Mediated Oxidative Stress In Vitro and In Vivo. Circ Res 2005; 96(4):435-441. (16) Chen YH, Lin SJ, Lin MW, Tsai HL, Kuo SS, Chen JW et al. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 2002; 111(1):1-8. (17) Chen YH, Chau LY, Chen JW, Lin SJ. Serum Bilirubin and Ferritin Levels Link Between Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients. Diabetes Care 2008;dc07-2126. (18) Sullivan J. Macrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability. Exp Biol Med 2007; 232(8):1014-1020. (19) Pirart J, Barbier P. [Protective effects of hemochromatosis against senile and diabetic angiopathies]. Diabetologia 1971; 7(4):227-236. (20) Sullivan JL, Till GO, Ward PA, Newton RB. Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr Res 1989; 9:625-634. (21) Murakawa H, Bland CE, Willis WT, Dallman PR. Iron deficiency and neutrophil function: different rates of correction of the depressions in oxidative burst and myeloperoxidase activity after iron treatment. Blood 1987; 69(5):1464-1468. (22) Uritski R, Barshack I, Bilkis I, Ghebremeskel K, Reifen R. Dietary Iron Affects Inflammatory Status in a Rat Model of Colitis. J Nutr 2004; 134(9):2251-2255.
Intraplaque iron as a modifiable atherogenic factor.
1 July 2009
Comment on: Tavora F, et al. BMC Cardiovascular Disorders 2009; 9(1):27.
The significance of the findings of Tavora et al (1) on iron and myeloperoxidase in unstable atherosclerotic plaques is best appreciated in the context of the growing literature on the role of iron as a modifiable risk factor for atherosclerosis (2). The study also provides evidence compatible with the "iron/heart hypothesis" that postulates a protective effect of iron depletion against cardiovascular disease (3-5).
Significant increases in iron concentration are present in human atherosclerotic lesions and in lesions in cholesterol fed animals in comparison to levels in the healthy arterial wall (6-8). Iron concentration (7) and induction of ferritin expression (9) are increased in very early lesions in cholesterol fed rabbits. Systemic iron reduction can decrease the intraplaque concentration of iron (10). In recent animal studies, depletion of lesion iron levels in vivo by phlebotomy, systemic iron chelation treatment or dietary iron restriction reduces lesion size and/or increases plaque stability (10-12).
A study of ex vivo human carotid atherosclerotic lesions found transferrin receptor 1 (TfR1) expression positively correlated with macrophage infiltration, ectopic lysosomal cathepsin L and ferritin expression (13). Highly expressed TfR1 and ferritin in CD68 positive macrophages were significantly associated with development and severity of human carotid plaques. The findings suggest that pathologic macrophage iron metabolism may contribute to vulnerability of human atheroma.
Several factors associated with increased arterial disease or increased cardiovascular events are also associated with increased plaque iron. Infusion of angiotensin II in rats increases ferritin levels and arterial thickness (14). These changes are reversed by treatment with the iron chelator deferoxamine. A human polymorphism for haptoglobin associated with increased cardiovascular disease is characterized by increased lesional iron (15). Heme oxygenase 1 (HO1) is a key component of the system for mobilization of iron from macrophages. Human HO1 promoter polymorphisms associated with weaker upregulation of the enzyme are associated with increased cardiovascular disease (16;17). The hormone hepcidin promotes retention of iron within macrophages and is upregulated by inflammation-induced synthesis of IL-6. The association of cardiovascular disease with inflammation may be in part caused by elevated hepcidin levels that promote retention of iron within plaque macrophages (2).
Iron depletion has been proposed as a protective factor against cardiovascular disease. Increasing evidence suggests that an important mechanism for this protection involves a reduction in iron levels within atherosclerotic plaque. Diminished hepcidin levels and defective retention of iron within arterial macrophages in genetic hemochromatosis may explain why there is little evidence of increased atherosclerosis in this disorder despite systemic iron overload (18). Protection against atherosclerotic lesions in hemochromatosis has been reported (19).
Tavora et al (1) suggest that the molecular relationship between iron and myeloperoxidase is unknown although they recognize that myeloperoxidase contains iron. It appears possible that myeloperoxidase activity is decreased in iron deficiency (20-22). Iron could be a limiting factor for myeloperoxidase formation at very low iron levels. Diminished inflammatory injury in association with reduction in myeloperoxidase activity by induced iron deficiency was first reported 20 years ago (20). Myeloperoxidase is thus a potentially modifiable coronary risk factor. Future studies are needed to determine if induced depletion of plaque iron can also lower intraplaque myeloperoxidase levels.
Jerome L. Sullivan, MD, PhD
University of Central Florida College of Medicine
jlsullivan3@gmail.com
(1) Tavora F, Ripple M, Li L, Burke A. Monocytes and neutrophils expressing myeloperoxidase occur in fibrous caps and thrombi in unstable coronary plaques. BMC Cardiovascular Disorders 2009; 9(1):27.
(2) Sullivan JL. Iron in arterial plaque: A modifiable risk factor for atherosclerosis. Biochim Biophys Acta - General Subjects 2009; 1790(7):718-723.
(3) Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981; 1(8233):1293-1294.
(4) Sullivan JL. The iron paradigm of ischemic heart disease. Am Heart J 1989; 117(5):1177-1188.
(5) Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003; 145(2):190-194.
(6) Stadler N, Lindner RA, Davies MJ. Direct Detection and Quantification of Transition Metal Ions in Human Atherosclerotic Plaques: Evidence for the Presence of Elevated Levels of Iron and Copper. Arterioscler Thromb Vasc Biol 2004; 24(5):949-954.
(7) Ponraj D, Makjanic J, Thong PS, Tan BK, Watt F. The onset of atherosclerotic lesion formation in hypercholesterolemic rabbits is delayed by iron depletion. FEBS Lett 1999; 459(2):218-222.
(8) Raman SV, Winner MW, III, Tran T, Velayutham M, Simonetti OP, Baker PB et al. In Vivo Atherosclerotic Plaque Characterization Using Magnetic Susceptibility Distinguishes Symptom-Producing Plaques. J Am Coll Cardiol Img 2008; 1(1):49-57.
(9) Pang JH, Jiang MJ, Chen YL, Wang FW, Wang DL, Chu SH et al. Increased ferritin gene expression in atherosclerotic lesions. J Clin Invest 1996; 97(10):2204-2212.
(10) Minqin R, Rajendran R, Pan N, Kwong-Huat TB, Ong WY, Watt F et al. The iron chelator desferrioxamine inhibits atherosclerotic lesion development and decreases lesion iron concentrations in the cholesterol-fed rabbit. Free Radic Biol Med 2005; 38(9):1206-1211.
(11) Lee TS, Shiao MS, Pan CC, Chau LY. Iron-deficient diet reduces atherosclerotic lesions in apoE-deficient mice. Circulation 1999; 99(9):1222-1229.
(12) Lee HT, Chiu LL, Lee TS, Tsai HL, Chau LY. Dietary iron restriction increases plaque stability in apolipoprotein-e-deficient mice. J Biomed Sci 2003; 10(5):510-517.
(13) Li W, Xu LH, Forssell C, Sullivan JL, Yuan XM. Overexpression of Transferrin Receptor and Ferritin Related to Clinical Symptoms and Destabilization of Human Carotid Plaques. Exp Biol Med 2008; 233(7):818-826.
(14) Ishizaka N, Saito K, Mori I, Matsuzaki G, Ohno M, Nagai R. Iron Chelation Suppresses Ferritin Upregulation and Attenuates Vascular Dysfunction in the Aorta of Angiotensin II-Infused Rats. Arterioscler Thromb Vasc Biol 2005; 25(11):2282-2288.
(15) Asleh R, Guetta J, Kalet-Litman S, Miller-Lotan R, Levy AP. Haptoglobin Genotype- and Diabetes-Dependent Differences in Iron-Mediated Oxidative Stress In Vitro and In Vivo. Circ Res 2005; 96(4):435-441.
(16) Chen YH, Lin SJ, Lin MW, Tsai HL, Kuo SS, Chen JW et al. Microsatellite polymorphism in promoter of heme oxygenase-1 gene is associated with susceptibility to coronary artery disease in type 2 diabetic patients. Hum Genet 2002; 111(1):1-8.
(17) Chen YH, Chau LY, Chen JW, Lin SJ. Serum Bilirubin and Ferritin Levels Link Between Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients. Diabetes Care 2008;dc07-2126.
(18) Sullivan J. Macrophage Iron, Hepcidin, and Atherosclerotic Plaque Stability. Exp Biol Med 2007; 232(8):1014-1020.
(19) Pirart J, Barbier P. [Protective effects of hemochromatosis against senile and diabetic angiopathies]. Diabetologia 1971; 7(4):227-236.
(20) Sullivan JL, Till GO, Ward PA, Newton RB. Nutritional iron restriction diminishes acute complement-dependent lung injury. Nutr Res 1989; 9:625-634.
(21) Murakawa H, Bland CE, Willis WT, Dallman PR. Iron deficiency and neutrophil function: different rates of correction of the depressions in oxidative burst and myeloperoxidase activity after iron treatment. Blood 1987; 69(5):1464-1468.
(22) Uritski R, Barshack I, Bilkis I, Ghebremeskel K, Reifen R. Dietary Iron Affects Inflammatory Status in a Rat Model of Colitis. J Nutr 2004; 134(9):2251-2255.
Competing interests
None