铁代谢与动脉硬化的发生发展
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摘要
铁元素是多种蛋白及酶的辅助元素。动脉硬化(atherosclerosis,AS)是一种全身性慢性炎症性血管疾病。铁可以导致巨噬细胞中ROS产生增多,且会促进脂质过氧化,最终促进动脉粥样硬化的进展并降低斑块的稳定性。尽管铁在动脉粥样硬化中的作用已经比较清楚,但关于斑块处铁代谢紊乱的机制仍未清楚,本文对铁代谢与动脉硬化的相关性进行综述,旨在了解并阐述炎症、肥胖等动脉硬化的危险因素和铁代谢之间的关系,从而对动脉硬化的诊断及治疗有一定的启发。
Iron is an essential mineral in many proteins andenzymes in human physiology and is involved in various inflammation disease like atherosclerosis. Atherosclerosis is a chronic systemic inflammation disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Although iron is very important in atherosclerosis development, the detailed mechanism of iron obstruction in atherosclerosis plaque is unclear. This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches.
Iron is an essential mineral in many proteins andenzymes in human physiology and is involved in various inflammation disease like atherosclerosis. Atherosclerosis is a chronic systemic inflammation disease. In atherosclerosis, iron catalyzes the creation of reactive oxygen free radicals that contribute to lipid modification, which is essential to atheroma formation. Inflammation further fuels iron-related pathologic processes associated with plaque progression. Although iron is very important in atherosclerosis development, the detailed mechanism of iron obstruction in atherosclerosis plaque is unclear. This review summarizes the role of iron in atherosclerosis with considerable implications for novel diagnostic and therapeutic approaches.
引文
[1]王红柳,张钟爱,骆天炯.下肢动脉粥样硬化性疾病的流行病学及危险因素研究[J].吉林中医药,2012,32(10):1006-1008.
[2]谢晓亮.上海、内蒙古自然人群臂踝脉搏波速度与踝臂指数的调查研究[D].上海:同济大学医学院,2009.
[3]Sullivan J.Iron and the sex difference in heart diseaserisk[J].The Lancet.1981,317(8233):1293-1294.
[4]Sullivan JL.Are menstruating women protected from heart disease because of,or in spite of,estrogen?Relevance to the iron hypothesis[J].American heart journal,2003,145(2):190-194.
[5]van Jaarsveld H,Pool GF.Beneficial effects of blood donation on high density lipoprotein concentration and the oxidative potential of low density lipoprotein[J].Atherosclerosis,2002,161(2):395-402.
[6]Fernández-Real JM,Manco M.Effects of iron overload on chronic metabolic diseases[J].The Lancet Diabetes&Endocrinology,2014,2(6):513-526.
[7]Sung KC,Kang SM,Cho EJ,et al.Ferritin is independently associated with the presence of coronary artery calcium in 12,033 men[J].Arteriosclerosis,thrombosis,and vascular biology,2012,32(10):2525-2530.
[8]Z h a n g W J,We i H,F r e i B.T h e i r o n c h e l a t o r,desferrioxamine,reduces inflammation and atherosclerotic lesion development in experimental mice[J].Experimental biology and medicine,2010,235(5):633-641.
[9]Lioupis C,Barbatis C,Drougou A,et al.Association of haptoglobin genotype and common cardiovascular risk factors with the amount of iron in atherosclerotic carotid plaques[J].Atherosclerosis,2011,216(1):131-138.
[10]Nemeth E,Tuttle MS,Powelson J,et al.Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization[J].Science,2004,306(5704):2090-2093.
[11]Ganz T.Hepcidin,a key regulator of iron metabolism and mediator of anemia of inflammation[J].Blood,2003,102(3):783-788.
[12]Saeed O,Otsuka F,Polavarapu R,et al.Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis[J].Arterioscler Thromb Vasc Biol,2012,32(2):299-307.
[13]Habib A,Finn AV.The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis[J].Frontiers in pharmacology,2014,5:195.
[14]Galkina E,Ley K.Immune and inflammatory mechanisms of atherosclerosis[J].Annual review ofimmunology,2009,27:165-197.
[15]Crichton RR,Wilmet S,Legssyer R,et al.Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells[J].Journal of inorganic biochemistry,2002,91(1):9-18.
[16]Sakakura K,Nakano M,Otsuka F,et al.Pathophysiology of atherosclerosis plaque progression[J].Heart,lung&circulation,2013,22(6):399-411.
[17]Marcil V,Delvin E,Sane AT,et al.Oxidative stress influences cholesterol efflux in THP-1 macrophages:role of ATP-binding cassette A1 and nuclear factors[J].Cardiovascular research,2006,72(3):473-482.
[18]Finn AV,Nakano M,Polavarapu R,et al.Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques[J].J Am Coll Cardiol,2012,59(2):166-177.
[19]Zhang Z,Zhang F,An P,et al.Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses[J].Blood,2011,118(7):1912-1922.
[20]Kautz L,Gabayan V,Wang X,et al.Testing the iron hypothesis in a mouse model of atherosclerosis[J].Cell reports,2013,5(5):1436-1442.
[21]Seufert J.Leptin effects on pancreatic beta-cell gene expression and function[J].Diabetes,2004,53(Suppl1):S152-158.
[22]Naseem KM.The role of nitric oxide in cardiovascular diseases[J].Molecular aspects of medicine,2005,26(1-2):33-65.
[23]Koh KK.Effects of statins on vascular wall:vasomotor function,inflammation,and plaque stability[J].Cardiovascular research,2000,47(4):648-657.
[24]Loffreda S,Yang SQ,Lin HZ,et al.Leptin regulates proinflammatory immune responses[J].FASEB journal:official publication of the Federation of American Societies for Experimental Biology,1998,12(1):57-65.
[25]Yamagishi SI,Edelstein D,Du XL,et al.Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A[J].The Journal of biological chemistry,2001,276(27):25096-25100.
[26]Sanchez-Margalet V,Martin-Romero C,Santos-AlvarezJ,et al.Role of leptin as an immunomodulator of blood mononuclear cells:mechanisms of action[J].Clinical and experimental immunology,2003,133(1):11-19.
[27]Beltowski J.Leptin and atherosclerosis[J].Atherosclerosis,2006,189(1):47-60.
[28]Wenzel BJ,Stults HB,Mayer J.Hypoferraemia in obese adolescents[J].Lancet,1962,2(7251):327-328.
[29]Yanoff LB,Menzie CM,Denkinger B,et al.Inflammation and iron deficiency in the hypoferremia of obesity[J].Int J Obes,2007,31(9):1412-1419.
[30]Lecube A,Carrera A,Losada E,et al.Iron deficiency in obese postmenopausal women[J].Obesity,2006,14(10):1724-1730.
[31]Menzie CM,Yanoff LB,Denkinger BI,et al.Obesityrelated hypoferremia is not explained by differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption[J].Journal of the American Dietetic Association,2008,108(1):145-148.
[32]Sonnweber T,Ress C,Nairz M,et al.High-fat diet causes iron deficiency via hepcidin-independent reduction of duodenal iron absorption[J].The Journal of nutritional biochemistry,2012,23(12):1600-1608.
[33]Tussing-Humphreys LM,Liang H,Nemeth E,et al.Excess adiposity,inflammation,and iron-deficiency in female adolescents[J].Journal of the American Dietetic Association,2009,109(2):297-302.
[34]Pyorala K,Laakso M,Uusitupa M.Diabetes and atherosclerosis:an epidemiologic view[J].Diabetes/metabolism reviews,1987,3(2):463-524.
[35]Pencina MJ,D'Agostino RB Sr,Larson MG,et al.Predicting the 30-year risk of cardiovascular disease:the framingham heart study[J].Circulation,2009,119(24):3078-3084.
[36]卞茸文,顾刘宝,吕利萍,等.2型糖尿病患者外周血管病变与颈动脉粥样硬化的关系[J].中国糖尿病杂志,2007,15(8):478-480.
[37]Sun L,Zong G,Pan A,et al.Elevated Plasma Ferritin Is Associated with Increased Incidence of Type 2 Diabetes in Middle-Aged and Elderly Chinese Adults[J].The Journal of Nutrition,2013,143(9):1459-1465.
[38]Salonen JT,Tuomainen T-P,Nyyssonen K,et al.Relation between iron stores and non-insulin dependent diabetesin men:case-control study[J].BMJ,1998,317(7160):727-730.
[39]Fernández-Real JM,Penarroja G,Castro A,et al.Blood Letting in High-Ferritin Type 2 Diabetes:Effects on Insulin Sensitivity andβ-Cell Function[J].Diabetes,2002,51(4):1000-1004.
[40]Niederau C,Berger M,Stremmel W,et al.Hyperinsulinaemia in non-cirrhotic haemochromatosis:impaired hepatic insulin degradation?[J].Diabetologia,1984,26(6):441-444.
[41]Mendler M-H,Turlin B,Moirand R,et al.Insulin resistance–associated hepatic iron overload[J].Gastroenterology,1999,117(5):1155-1163.
[42]Fernandez-Cao JC,Arija V,Aranda N,et al.Heme iron intake and risk of new-onset diabetes in a Mediterranean population at high risk of cardiovascular disease:an observational cohort analysis[J].BMC public health,2013,13:1042.
[43]Luan DC,Li H,Li SJ,et al.Body Iron Stores and Dietary Iron Intake in Relation to Diabetes in Adults in North China[J].Diabetes Care,2008,31(2):285-286.
[44]Jiang R,Manson JE,Meigs JB,et al.BOdy iron stores in relation to risk of type 2 diabetes in apparently healthy women[J].JAMA,2004,291(6):711-717.
[45]Pan A,Sun Q,Bernstein AM,et al.Red meat consumption and risk of type 2 diabetes:3 cohorts of US adults and an updated meta-analysis[J].The American Journal of Clinical Nutrition,2011,94(4):1088-1096.
[46]Huang J,Jones D,Luo B,et al.Iron Overload and Diabetes Risk:A Shift From Glucose to Fatty Acid Oxidation and Increased Hepatic Glucose Production in a Mouse Model of Hereditary Hemochromatosis[J].Diabetes,2011,60(1):80-87.
[47]Mc Carthy MJ,Loftus IM,Thompson MM,et al.Angiogenesis and the atherosclerotic carotid plaque:An association between symptomatology and plaque morphology[J].Journal of Vascular Surgery,1999,30(2):261-268.
[48]Moreno PR,Fuster V.New aspects in the pathogenesis of diabetic atherothrombosis[J].Journal of the American College of Cardiology,2004,44(12):2293-2300.
[49]马小龙,陆建平,刘崎,等.超微超顺磁性氧化铁和钆对比剂增强兔动脉硬化斑块之比较[J].放射学实践,2009,24(9):976-981.
[50]Sharkey-Toppen TP,Tewari AK,Raman SV.Iron and atherosclerosis:nailing down a novel target with magnetic resonance[J].Journal of cardiovascular translational research,2014,7(5):533-542.
[51]Howarth SPS,Li Z-Y,Tang TY,et al.In Vivo Positive Contrast IRON Sequence and Quantitative T2*Measurement Confirms Inflammatory Burden in a Patient with Asymptomatic Carotid Atheroma after USPIO-enhanced MR Imaging[J].Journal of Vascular and Interventional Radiology,2008,19(3):446-448.
[52]Patterson AJ,Tang TY,Graves MJ,et al.In vivo carotid plaque MRI using quantitative T2*measurements with ultrasmall superparamagnetic iron oxide particles:a doseresponse study to statin therapy[J].NMR in biomedicine,2011,24(1):89-95.
[2]谢晓亮.上海、内蒙古自然人群臂踝脉搏波速度与踝臂指数的调查研究[D].上海:同济大学医学院,2009.
[3]Sullivan J.Iron and the sex difference in heart diseaserisk[J].The Lancet.1981,317(8233):1293-1294.
[4]Sullivan JL.Are menstruating women protected from heart disease because of,or in spite of,estrogen?Relevance to the iron hypothesis[J].American heart journal,2003,145(2):190-194.
[5]van Jaarsveld H,Pool GF.Beneficial effects of blood donation on high density lipoprotein concentration and the oxidative potential of low density lipoprotein[J].Atherosclerosis,2002,161(2):395-402.
[6]Fernández-Real JM,Manco M.Effects of iron overload on chronic metabolic diseases[J].The Lancet Diabetes&Endocrinology,2014,2(6):513-526.
[7]Sung KC,Kang SM,Cho EJ,et al.Ferritin is independently associated with the presence of coronary artery calcium in 12,033 men[J].Arteriosclerosis,thrombosis,and vascular biology,2012,32(10):2525-2530.
[8]Z h a n g W J,We i H,F r e i B.T h e i r o n c h e l a t o r,desferrioxamine,reduces inflammation and atherosclerotic lesion development in experimental mice[J].Experimental biology and medicine,2010,235(5):633-641.
[9]Lioupis C,Barbatis C,Drougou A,et al.Association of haptoglobin genotype and common cardiovascular risk factors with the amount of iron in atherosclerotic carotid plaques[J].Atherosclerosis,2011,216(1):131-138.
[10]Nemeth E,Tuttle MS,Powelson J,et al.Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization[J].Science,2004,306(5704):2090-2093.
[11]Ganz T.Hepcidin,a key regulator of iron metabolism and mediator of anemia of inflammation[J].Blood,2003,102(3):783-788.
[12]Saeed O,Otsuka F,Polavarapu R,et al.Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis[J].Arterioscler Thromb Vasc Biol,2012,32(2):299-307.
[13]Habib A,Finn AV.The role of iron metabolism as a mediator of macrophage inflammation and lipid handling in atherosclerosis[J].Frontiers in pharmacology,2014,5:195.
[14]Galkina E,Ley K.Immune and inflammatory mechanisms of atherosclerosis[J].Annual review ofimmunology,2009,27:165-197.
[15]Crichton RR,Wilmet S,Legssyer R,et al.Molecular and cellular mechanisms of iron homeostasis and toxicity in mammalian cells[J].Journal of inorganic biochemistry,2002,91(1):9-18.
[16]Sakakura K,Nakano M,Otsuka F,et al.Pathophysiology of atherosclerosis plaque progression[J].Heart,lung&circulation,2013,22(6):399-411.
[17]Marcil V,Delvin E,Sane AT,et al.Oxidative stress influences cholesterol efflux in THP-1 macrophages:role of ATP-binding cassette A1 and nuclear factors[J].Cardiovascular research,2006,72(3):473-482.
[18]Finn AV,Nakano M,Polavarapu R,et al.Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques[J].J Am Coll Cardiol,2012,59(2):166-177.
[19]Zhang Z,Zhang F,An P,et al.Ferroportin1 deficiency in mouse macrophages impairs iron homeostasis and inflammatory responses[J].Blood,2011,118(7):1912-1922.
[20]Kautz L,Gabayan V,Wang X,et al.Testing the iron hypothesis in a mouse model of atherosclerosis[J].Cell reports,2013,5(5):1436-1442.
[21]Seufert J.Leptin effects on pancreatic beta-cell gene expression and function[J].Diabetes,2004,53(Suppl1):S152-158.
[22]Naseem KM.The role of nitric oxide in cardiovascular diseases[J].Molecular aspects of medicine,2005,26(1-2):33-65.
[23]Koh KK.Effects of statins on vascular wall:vasomotor function,inflammation,and plaque stability[J].Cardiovascular research,2000,47(4):648-657.
[24]Loffreda S,Yang SQ,Lin HZ,et al.Leptin regulates proinflammatory immune responses[J].FASEB journal:official publication of the Federation of American Societies for Experimental Biology,1998,12(1):57-65.
[25]Yamagishi SI,Edelstein D,Du XL,et al.Leptin induces mitochondrial superoxide production and monocyte chemoattractant protein-1 expression in aortic endothelial cells by increasing fatty acid oxidation via protein kinase A[J].The Journal of biological chemistry,2001,276(27):25096-25100.
[26]Sanchez-Margalet V,Martin-Romero C,Santos-AlvarezJ,et al.Role of leptin as an immunomodulator of blood mononuclear cells:mechanisms of action[J].Clinical and experimental immunology,2003,133(1):11-19.
[27]Beltowski J.Leptin and atherosclerosis[J].Atherosclerosis,2006,189(1):47-60.
[28]Wenzel BJ,Stults HB,Mayer J.Hypoferraemia in obese adolescents[J].Lancet,1962,2(7251):327-328.
[29]Yanoff LB,Menzie CM,Denkinger B,et al.Inflammation and iron deficiency in the hypoferremia of obesity[J].Int J Obes,2007,31(9):1412-1419.
[30]Lecube A,Carrera A,Losada E,et al.Iron deficiency in obese postmenopausal women[J].Obesity,2006,14(10):1724-1730.
[31]Menzie CM,Yanoff LB,Denkinger BI,et al.Obesityrelated hypoferremia is not explained by differences in reported intake of heme and nonheme iron or intake of dietary factors that can affect iron absorption[J].Journal of the American Dietetic Association,2008,108(1):145-148.
[32]Sonnweber T,Ress C,Nairz M,et al.High-fat diet causes iron deficiency via hepcidin-independent reduction of duodenal iron absorption[J].The Journal of nutritional biochemistry,2012,23(12):1600-1608.
[33]Tussing-Humphreys LM,Liang H,Nemeth E,et al.Excess adiposity,inflammation,and iron-deficiency in female adolescents[J].Journal of the American Dietetic Association,2009,109(2):297-302.
[34]Pyorala K,Laakso M,Uusitupa M.Diabetes and atherosclerosis:an epidemiologic view[J].Diabetes/metabolism reviews,1987,3(2):463-524.
[35]Pencina MJ,D'Agostino RB Sr,Larson MG,et al.Predicting the 30-year risk of cardiovascular disease:the framingham heart study[J].Circulation,2009,119(24):3078-3084.
[36]卞茸文,顾刘宝,吕利萍,等.2型糖尿病患者外周血管病变与颈动脉粥样硬化的关系[J].中国糖尿病杂志,2007,15(8):478-480.
[37]Sun L,Zong G,Pan A,et al.Elevated Plasma Ferritin Is Associated with Increased Incidence of Type 2 Diabetes in Middle-Aged and Elderly Chinese Adults[J].The Journal of Nutrition,2013,143(9):1459-1465.
[38]Salonen JT,Tuomainen T-P,Nyyssonen K,et al.Relation between iron stores and non-insulin dependent diabetesin men:case-control study[J].BMJ,1998,317(7160):727-730.
[39]Fernández-Real JM,Penarroja G,Castro A,et al.Blood Letting in High-Ferritin Type 2 Diabetes:Effects on Insulin Sensitivity andβ-Cell Function[J].Diabetes,2002,51(4):1000-1004.
[40]Niederau C,Berger M,Stremmel W,et al.Hyperinsulinaemia in non-cirrhotic haemochromatosis:impaired hepatic insulin degradation?[J].Diabetologia,1984,26(6):441-444.
[41]Mendler M-H,Turlin B,Moirand R,et al.Insulin resistance–associated hepatic iron overload[J].Gastroenterology,1999,117(5):1155-1163.
[42]Fernandez-Cao JC,Arija V,Aranda N,et al.Heme iron intake and risk of new-onset diabetes in a Mediterranean population at high risk of cardiovascular disease:an observational cohort analysis[J].BMC public health,2013,13:1042.
[43]Luan DC,Li H,Li SJ,et al.Body Iron Stores and Dietary Iron Intake in Relation to Diabetes in Adults in North China[J].Diabetes Care,2008,31(2):285-286.
[44]Jiang R,Manson JE,Meigs JB,et al.BOdy iron stores in relation to risk of type 2 diabetes in apparently healthy women[J].JAMA,2004,291(6):711-717.
[45]Pan A,Sun Q,Bernstein AM,et al.Red meat consumption and risk of type 2 diabetes:3 cohorts of US adults and an updated meta-analysis[J].The American Journal of Clinical Nutrition,2011,94(4):1088-1096.
[46]Huang J,Jones D,Luo B,et al.Iron Overload and Diabetes Risk:A Shift From Glucose to Fatty Acid Oxidation and Increased Hepatic Glucose Production in a Mouse Model of Hereditary Hemochromatosis[J].Diabetes,2011,60(1):80-87.
[47]Mc Carthy MJ,Loftus IM,Thompson MM,et al.Angiogenesis and the atherosclerotic carotid plaque:An association between symptomatology and plaque morphology[J].Journal of Vascular Surgery,1999,30(2):261-268.
[48]Moreno PR,Fuster V.New aspects in the pathogenesis of diabetic atherothrombosis[J].Journal of the American College of Cardiology,2004,44(12):2293-2300.
[49]马小龙,陆建平,刘崎,等.超微超顺磁性氧化铁和钆对比剂增强兔动脉硬化斑块之比较[J].放射学实践,2009,24(9):976-981.
[50]Sharkey-Toppen TP,Tewari AK,Raman SV.Iron and atherosclerosis:nailing down a novel target with magnetic resonance[J].Journal of cardiovascular translational research,2014,7(5):533-542.
[51]Howarth SPS,Li Z-Y,Tang TY,et al.In Vivo Positive Contrast IRON Sequence and Quantitative T2*Measurement Confirms Inflammatory Burden in a Patient with Asymptomatic Carotid Atheroma after USPIO-enhanced MR Imaging[J].Journal of Vascular and Interventional Radiology,2008,19(3):446-448.
[52]Patterson AJ,Tang TY,Graves MJ,et al.In vivo carotid plaque MRI using quantitative T2*measurements with ultrasmall superparamagnetic iron oxide particles:a doseresponse study to statin therapy[J].NMR in biomedicine,2011,24(1):89-95.