Thromb Haemost 2012; 108(03): 435-442
DOI: 10.1160/TH12-04-0248
Theme Issue Article
Schattauer GmbH

Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: Detoxifying mechanisms and potential therapeutic options

Jose Luis Martin-Ventura
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Julio Madrigal-Matute
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Roxana Martinez-Pinna
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Priscila Ramos-Mozo
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Luis Miguel Blanco-Colio
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Juan Antonio Moreno
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Carlos Tarin
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Elena Burillo
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Carlos Ernesto Fernandez-Garcia
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Jesus Egido
1   Vascular Research Lab, IIS-Fundación Jiménez Diaz-Autonoma University, Madrid, Spain
,
Olivier Meilhac
2   Inserm, U698, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Bichat, Paris, France
,
Jean-Baptiste Michel
2   Inserm, U698, Université Paris Diderot, Sorbonne Paris Cité, AP-HP, Hôpital Bichat, Paris, France
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received: 18. April 2012

Accepted after minor revision: 21. Juni 2012

Publikationsdatum:
25. November 2017 (online)

Summary

Oxidative stress is involved in the chronic pathological vascular remodelling of both abdominal aortic aneurysm and occlusive atherosclerosis. Red blood cells (RBCs), leukocytes and platelets present in both, aneurysmal intraluminal thrombus and intraplaque haemorraghes, could be involved in the redox imbalance inside diseased arterial tissues. RBCs haemolysis may release the pro-oxidant haemoglobin (Hb), which transfers heme to tissue and low-density lipoproteins. Heme-iron potentiates molecular, cell and tissue toxicity mediated by leukocytes and other sources of reactive oxygen species (ROS). Polymorphonuclear neutrophils release myeloperoxidase and, along with activated platelets, produce superoxide mediated by NADPH oxidase, causing oxidative damage. In response to this pro-oxidant milieu, several anti-oxidant molecules of plasma or cell origin can prevent ROS production. Free Hb binds to haptoglobin (Hp) and once Hp-Hb complex is endocytosed by CD163, liberated heme is converted into less toxic compounds by heme oxygenase-1. Iron homeostasis is mainly regulated by transferrin, which transports ferric ions to other cells. Transferrin-bound iron is internalised via endocytosis mediated by transferrin receptor. Once inside the cell, iron is mainly stored by ferritin. Other non hemo-iron related antioxidant enzymes (e.g. superoxide dismutase, catalase, thioredoxin and peroxiredoxin) are also involved in redox modulation in vascular remodelling. Oxidative stress is a main determinant of chronic pathological remodelling of the arterial wall, partially linked to the presence of RBCs, leukocytes, platelets and oxidised fibrin within tissue and to the imbalance between pro-/anti-oxidant molecules. Understanding the complex mechanisms underlying redox imbalance could help to define novel potential targets to decrease atherothrombotic risk.

 
  • References

  • 1 Michel JB. et al. Novel aspects of the pathogenesis of aneurysms of the abdominal aorta in humans. Cardiovasc Res 2011; 90: 18-27.
  • 2 Farbstein D. et al. Genetics of redox systems and their relationship with cardiovascular disease. Curr Atheroscler Rep 2011; 13: 215-224.
  • 3 Undas A. et al. Reduced clot permeability and susceptibility to lysis in patients with acute coronary syndrome: effects of inflammation and oxidative stress. Atherosclerosis 2008; 196: 551-557.
  • 4 Silvain J. et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 1359-1367.
  • 5 Yunoki K. et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33: 1480-1490.
  • 6 Kolodgie FD. et al. Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003; 349: 2316-2325.
  • 7 Nagy E. et al. Red cells, hemoglobin, heme, iron, and atherogenesis. Arterioscler Thromb Vasc Biol 2010; 30: 1347-1353.
  • 8 Buttari B. et al. Free hemoglobin: a dangerous signal for the immune system in patients with carotid atherosclerosis?. Ann NY Acad Sci 2007; 1107: 42-50.
  • 9 Silva G. et al. Oxidized hemoglobin is an endogenous proinflammatory agonist that targets vascular endothelial cells. J Biol Chem 2009; 284: 29582-29595.
  • 10 Boyle JJ. et al. Coronary intraplaque hemorrhage evokes a novel atheroprotective macrophage phenotype. Am J Pathol 2009; 174: 1097-1108.
  • 11 Boyle JJ. et al. Heme Induces Heme Oxygenase 1 via Nrf2: Role in the Homeostatic Macrophage Response to Intraplaque Hemorrhage. Arterioscler Thromb Vasc Biol 2011; 31: 2685-2691.
  • 12 Boyle JJ. et al. Activating transcription factor 1 directs Mhem atheroprotective macrophages through coordinated iron handling and foam cell protection. Circ Res 2012; 110: 20-33.
  • 13 Finn AV. et al. Hemoglobin directs macrophage differentiation and prevents foam cell formation in human atherosclerotic plaques. J Am Coll Cardiol 2012; 59: 166-177.
  • 14 Watanabe J. et al. Differential association of hemoglobin with proinflammatory high density lipoproteins in atherogenic/hyperlipidemic mice. A novel biomarker of atherosclerosis. J Biol Chem 2007; 282: 23698-23707.
  • 15 Crawford JH. et al. Hypoxia, red blood cells, and nitrite regulate NO-dependent hypoxic vasodilation. Blood 2006; 107: 566-574.
  • 16 Minneci PC. et al. Nitrite reductase activity of hemoglobin as a systemic nitric oxide generator mechanism to detoxify plasma hemoglobin produced during hemolysis. Am J Physiol Heart Circ Physiol 2008; 295: H743-H754.
  • 17 Tolosano E. et al. Heme scavenging and the other facets of hemopexin. Antioxid Redox Signal 2010; 12: 305-320.
  • 18 Kumar S, Bandyopadhyay U. Free heme toxicity and its detoxification systems in human. Toxicol Lett 2005; 157: 175-188.
  • 19 Balla J. et al. Heme, heme oxygenase, and ferritin: how the vascular endothelium survives (and dies) in an iron-rich environment. Antioxid Redox Signal 2007; 09: 2119-2137.
  • 20 Porto BN. et al. Heme induces neutrophil migration and reactive oxygen species generation through signaling pathways characteristic of chemotactic receptors. J Biol Chem 2007; 282: 24430-24436.
  • 21 Monteiro AP. et al. Leukotriene B4 mediates neutrophil migration induced by heme. J Immunol 2011; 186: 6562-6567.
  • 22 Jeney V. et al. Pro-oxidant and cytotoxic effects of circulating heme. Blood 2002; 100: 879-887.
  • 23 Ball RY. et al. Oxidized low density lipoprotein induces ceroid accumulation by murine peritoneal macrophages in vitro. Atherosclerosis 1986; 60: 173-181.
  • 24 Ball RY. et al. What is the significance of ceroid in human atherosclerosis?. Arch Pathol Lab Med 1987; 111: 1134-1140.
  • 25 Lee FY. et al. Colocalization of iron and ceroid in human atherosclerotic lesions. Atherosclerosis 1998; 138: 281-288.
  • 26 Haka AS. et al. Mechanism of ceroid formation in atherosclerotic plaque: in situ studies using a combination of Raman and fluorescence spectroscopy. J Biomed Opt 2011; 16: 011011.
  • 27 Brissot P. et al. Non-transferrin bound iron: A key role in iron overload and iron toxicity. Biochim Biophys Acta 2012; 1820: 403-410.
  • 28 Ray PD. et al. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 2012; 24: 981-990.
  • 29 Stadler N. et al. 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: 949-954.
  • 30 Stanley N. et al. Concentrations of iron correlate with the extent of protein, but not lipid, oxidation in advanced human atherosclerotic lesions. Free Radic Biol Med 2006; 40: 1636-1643.
  • 31 Arslan C. et al. Trace elements and toxic heavy metals play a role in Buerger disease and atherosclerotic peripheral arterial occlusive disease. Int Angiol 2010; 29: 489-495.
  • 32 Nchimi A. et al. MR imaging of iron phagocytosis in intraluminal thrombi of abdominal aortic aneurysms in humans. Radiology 2010; 254: 973-981.
  • 33 Li JM, Shah AM. Endothelial cell superoxide generation: regulation and relevance for cardiovascular pathophysiology. Am J Physiol Regul Integr Comp Physiol 2004; 287: R1014-R1030.
  • 34 Guzik TJ. et al. Coronary artery superoxide production and nox isoform expression in human coronary artery disease. Arterioscler Thromb Vasc Biol 2006; 26: 333-339.
  • 35 Miller Jr FJ. et al. Oxidative stress in human abdominal aortic aneurysms: a potential mediator of aneurysmal remodeling. Arterioscler Thromb Vasc Biol 2002; 22: 560-565.
  • 36 Ramos-Mozo P. et al. Proteomic analysis of polymorphonuclear neutrophils identifies catalase as a novel biomarker of abdominal aortic aneurysm: potential implication of oxidative stress in abdominal aortic aneurysm progression. Arterioscler Thromb Vasc Biol 2011; 31: 3011-3019.
  • 37 Suvorava T, Kojda G. Reactive oxygen species as cardiovascular mediators: lessons from endothelial-specific protein overexpression mouse models. Biochim Biophys Acta 2009; 1787: 802-810.
  • 38 Lassegue B, Clempus RE. Vascular NAD(P)H oxidases: specific features, expression, and regulation. Am J Physiol Regul Integr Comp Physiol 2003; 285: R277-R297.
  • 39 Zalba G. et al. NADPH oxidase-dependent superoxide production is associated with carotid intima-media thickness in subjects free of clinical atherosclerotic disease. Arterioscler Thromb Vasc Biol 2005; 25: 1452-1457.
  • 40 Davies MJ. Myeloperoxidase-derived oxidation: mechanisms of biological damage and its prevention. J Clin Biochem Nutr 2011; 48: 8-19.
  • 41 van der Veen BS. et al. Myeloperoxidase: molecular mechanisms of action and their relevance to human health and disease. Antioxid Redox Signal 2009; 11: 2899-2937.
  • 42 Domigan NM. et al. Chlorination of tyrosyl residues in peptides by myeloperoxidase and human neutrophils. J Biol Chem 1995; 270: 16542-16548.
  • 43 Skaff O. et al. Hypothiocyanous acid reactivity with low-molecular-mass and protein thiols: absolute rate constants and assessment of biological relevance. Biochem J 2009; 422: 111-117.
  • 44 Skaff O. et al. Selenium-containing amino acids are targets for myeloperoxidase-derived hypothiocyanous acid: determination of absolute rate constants and implications for biological damage. Biochem J 2012; 441: 305-316.
  • 45 Eiserich JP. et al. Formation of nitric oxide-derived inflammatory oxidants by myeloperoxidase in neutrophils. Nature 1998; 391: 393-397.
  • 46 Gaut JP. et al. Myeloperoxidase produces nitrating oxidants in vivo. J Clin Invest 2002; 109: 1311-1319.
  • 47 Galijasevic S. et al. Myeloperoxidase interaction with peroxynitrite: chloride deficiency and heme depletion. Free Radic Biol Med 2009; 47: 431-439.
  • 48 Shao B. et al. Oxidation of apolipoprotein A-I by myeloperoxidase impairs the initial interactions with ABCA1 required for signaling and cholesterol export. J Lipid Res 2010; 51: 1849-1858.
  • 49 Daugherty A. et al. Myeloperoxidase, a catalyst for lipoprotein oxidation, is expressed in human atherosclerotic lesions. J Clin Invest 1994; 94: 437-444.
  • 50 Martin-Ventura JL. et al. Low plasma levels of HSP70 in patients with carotid atherosclerosis are associated with increased levels of proteolytic markers of neutrophil activation. Atherosclerosis 2007; 194: 334-341.
  • 51 Houard X. et al. Mediators of neutrophil recruitment in human abdominal aortic aneurysms. Cardiovasc Res 2009; 82: 532-541.
  • 52 Stokes KY. et al. Platelet-associated NAD(P)H oxidase contributes to the thrombogenic phenotype induced by hypercholesterolemia. Free Radic Biol Med 2007; 43: 22-30.
  • 53 Krotz F. et al. NAD(P)H oxidase-dependent platelet superoxide anion release increases platelet recruitment. Blood 2002; 100: 917-924.
  • 54 Siegel-Axel D. et al. Platelet lipoprotein interplay: trigger of foam cell formation and driver of atherosclerosis. Cardiovasc Res 2008; 78: 8-17.
  • 55 Carnevale R. et al. LDL are oxidatively modified by platelets via GP91(phox) and accumulate in human monocytes. FASEB J 2007; 21: 927-934.
  • 56 Podrez EA. et al. Platelet CD36 links hyperlipidemia, oxidant stress and a prothrombotic phenotype. Nat Med 2007; 13: 1086-1095.
  • 57 Assinger A. et al. Hypochlorite-oxidized LDL induces intraplatelet ROS formation and surface exposure of CD40L--a prominent role of CD36. Atherosclerosis 2010; 213: 129-134.
  • 58 Wang H. et al. Oxidized low-density lipoprotein-dependent platelet-derived microvesicles trigger procoagulant effects and amplify oxidative stress. Mol Med 2012; 18: 159-166.
  • 59 Bini A. et al. Identification and distribution of fibrinogen, fibrin, and fibrin(ogen) degradation products in atherosclerosis. Use of monoclonal antibodies. Arteriosclerosis 1989; 09: 109-121.
  • 60 Undas A, Ariens RA. Fibrin clot structure and function: a role in the pathophysiology of arterial and venous thromboembolic diseases. Arterioscler Thromb Vasc Biol 2011; 31: e88-e99.
  • 61 Feng YH, Hart G. In vitro oxidative damage to tissue-type plasminogen activator: a selective modification of the biological functions. Cardiovasc Res 1995; 30: 255-261.
  • 62 Thompson SG. et al. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group. N Engl J Med 1995; 332: 635-641.
  • 63 Yamazumi K. et al. An activated state of blood coagulation and fibrinolysis in patients with abdominal aortic aneurysm. Am J Surg 1998; 175: 297-301.
  • 64 Parastatidis I. et al. Fibrinogen beta-chain tyrosine nitration is a prothrombotic risk factor. J Biol Chem 2008; 283: 33846-33853.
  • 65 Paton LN. et al. Increased thrombin-induced polymerization of fibrinogen associated with high protein carbonyl levels in plasma from patients post myocardial infarction. Free Radic Biol Med 2010; 48: 223-229.
  • 66 Selmeci L. Advanced oxidation protein products (AOPP): novel uremic toxins, or components of the non-enzymatic antioxidant system of the plasma proteome?. Free Radic Res 2011; 45: 1115-1123.
  • 67 Buehler PW. et al. Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification. Blood 2009; 113: 2578-2586.
  • 68 Levy AP. et al. Haptoglobin: basic and clinical aspects. Antioxid Redox Signal 2010; 12: 293-304.
  • 69 Watanabe J. et al. Hemoglobin and its scavenger protein haptoglobin associate with apoA-1-containing particles and influence the inflammatory properties and function of high density lipoprotein. J Biol Chem 2009; 284: 18292-18301.
  • 70 Moreno PR. et al. Haptoglobin genotype is a major determinant of the amount of iron in the human atherosclerotic plaque. J Am Coll Cardiol 2008; 52: 1049-1051.
  • 71 Moreno JA. et al. In vitro and in vivo evidence for the role of elastase shedding of CD163 in human atherothrombosis. Eur Heart J 2012; 33: 252-263.
  • 72 Dulak J. et al. Effect of heme oxygenase-1 on vascular function and disease. Curr Opin Lipidol 2008; 19: 505-512.
  • 73 Ryter SW. et al. Heme oxygenase-1/carbon monoxide: from basic science to therapeutic applications. Physiol Rev 2006; 86: 583-650.
  • 74 Ishikawa K. et al. Induction of heme oxygenase-1 inhibits the monocyte transmigration induced by mildly oxidized LDL. J Clin Invest 1997; 100: 1209-1216.
  • 75 Nakahashi TK. et al. Flow loading induces macrophage antioxidative gene expression in experimental aneurysms. Arterioscler Thromb Vasc Biol 2002; 22: 2017-2022.
  • 76 Orozco LD. et al. Heme oxygenase-1 expression in macrophages plays a beneficial role in atherosclerosis. Circ Res 2007; 100: 1703-1711.
  • 77 Ishikawa K. et al. Heme oxygenase-1 inhibits atherosclerotic lesion formation in ldl-receptor knockout mice. Circ Res 2001; 88: 506-512.
  • 78 Arosio P, Levi S. Cytosolic and mitochondrial ferritins in the regulation of cellular iron homeostasis and oxidative damage. Biochim Biophys Acta 2010; 1800: 783-792.
  • 79 Wang W. et al. Serum ferritin: Past, present and futur. Biochim Biophys Acta 2010; 1800: 760-769.
  • 80 Sullivan JL. Iron in arterial plaque: modifiable risk factor for atherosclerosis. Biochim Biophys Acta 2009; 1790: 718-723.
  • 81 Li W. et al. Overexpression of transferrin receptor and ferritin related to clinical symptoms and destabilization of human carotid plaques. Exp Biol Med 2008; 233: 818-826.
  • 82 Altamura C. et al. Ceruloplasmin/Transferrin system is related to clinical status in acute stroke. Stroke 2009; 40: 1282-1288.
  • 83 Sinha I. et al. Differential regulation of the superoxide dismutase family in experimental aortic aneurysms and rat aortic explants. J Surg Res 2007; 138: 156-162.
  • 84 Dubick MA. et al. Antioxidant enzyme activity in human abdominal aortic aneurysmal and occlusive disease. Proc Soc Exp Biol Med 1999; 220: 39-45.
  • 85 Rhee SG, Woo HA. Multiple functions of peroxiredoxins: peroxidases, sensors and regulators of the intracellular messenger HO, and protein chaperones. Antioxid Redox Signal 2011; 15: 781-794.
  • 86 Nishihira K. et al. Thioredoxin in coronary culprit lesions: possible relationship to oxidative stress and intraplaque hemorrhage. Atherosclerosis 2008; 201: 360-367.
  • 87 Martinez-Pinna R. et al. Increased levels of thioredoxin in patients with abdominal aortic aneurysms (AAAs). A potential link of oxidative stress with AAA evolution. Atherosclerosis 2010; 212: 333-338.
  • 88 Martinez-Pinna R. et al. Identification of peroxiredoxin-1 as a novel biomarker of abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol 2011; 31: 935-943.
  • 89 Blankenberg S. et al. Glutathione peroxidase 1 activity and cardiovascular events in patients with coronary artery disease. N Engl J Med 2003; 349: 1605-1613.
  • 90 Espinola-Klein C. et al. Glutathione peroxidase-1 activity, atherosclerotic burden, and cardiovascular prognosis. Am J Cardiol 2007; 99: 808-812.
  • 91 Calzada C. et al. Decrease in platelet reduced glutathione increases lipoxygenase activity and decreases vitamin E. Lipids 1991; 26: 696-699.
  • 92 Minqin R. 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: 1206-1211.
  • 93 Saeed O. et al. Pharmacological suppression of hepcidin increases macrophage cholesterol efflux and reduces foam cell formation and atherosclerosis. Arterioscler Thromb Vasc Biol 2012; 32: 299-307.
  • 94 Pal C. et al. Synthesis of novel heme-interacting acridone derivatives to prevent free hememediated protein oxidation and degradation. Bioorg Med Chem Lett 2011; 21: 3563-3567.
  • 95 Xiong W. et al. Inhibition of reactive oxygen species attenuates aneurysm formation in a murine model. Atherosclerosis 2009; 202: 128-134.
  • 96 Grigoryants V. et al. Tamoxifen up-regulates catalase production, inhibits vessel wall neutrophil infiltration, and attenuates development of experimental abdominal aortic aneurysms. J Vasc Surg 2005; 41: 108-114.
  • 97 Chew P. et al. Site-specific antiatherogenic effect of the antioxidant ebselen in the diabetic apolipoprotein E-deficient mouse. Arterioscler Thromb Vasc Biol 2009; 29: 823-830.
  • 98 Sugamura K, Keaney Jr JF. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 2011; 51: 978-992.
  • 99 Milman U. et al. Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective double-blinded clinical trial. Arterioscler Thromb Vasc Biol 2008; 28: 341-347.
  • 100 Blum S. et al. The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Atherosclerosis 2010; 211: 25-27.
  • 101 Farbstein D. et al. Vitamin E therapy results in a reduction in HDL function in individuals with diabetes and the haptoglobin 2–1 genotype. Atherosclerosis 2011; 219: 240-244.