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Hyperhomocysteinemia due to Helicobacter pylori?
Atherosclerosis 176 (2004) 201–202
Letter to the Editor
Hyperhomocysteinemia due to Helicobacter pylori? Sir, We read with interest the letter by Khaled and Cornwell [1], who demonstrated that in subjects who were positive for Helicobacter pylori (H. pylori) there was increased plasma homocysteine (HCy) that did not appear to be due to reduced folate [1]. Given the evidence that viral and bacterial infection are associated with cadiovascular disease [2] and that HCy is an independent risk factor for CVD [3] these interrelationships have clear implications. We would like to add some comments and observations that may be of interest and relevance to this area. Firstly, infection is also associated with an elevation in the blood of the inflammation sensitive plasma proteins that include ceruloplasmin (CP) [5]. CP is a blood-borne protein that binds almost all the copper present in blood and which is itself an independent risk factor for CVD [4]. It has been known for some time that there is increased blood copper in patients with hyperhomocysteinaemia [6]. Plasma copper levels are also significantly correlated with elevated homocysteine levels in patients with peripheral arterial disease [7]. We found that following coronary artery bypass graft surgery (CABG), the blood levels of HCy and CP were increased for up to 6 weeks after surgery, indicating an association between CP, copper and HCy in the aetiology of vein graft failure [8]. Other studies have demonstrated that HCy and CP are elevated in patients with risk factors for CVD, in particular diabetes mellitus [9,10]. In a recent key study, Nakano et al. demonstrated that HCy binds avidly (chelates) copper [11]. It follows, therefore, that an increase in blood CP could result in an increase in HCy by virtue of the affinity of HCy for the copper associated with CP. In turn, this would explain why there are increased plasma levels of HCy in subjects with infection since CP is elevated in these patients. HCy and CP have been shown to interact in their own right to promote vasculopathy. For example, CP interacts with HCy through its copper moieties to promote the oxidation of low density lipoprotein [11]. Other studies have demonstrated that HCy and copper interact to generate reactive oxygen species including superoxide and hydrogen peroxide [12]. It is a widely held view that copper, due to its powerful pro-oxidant capacity, is 100% bound and as such not available for involvement in promoting oxidation-related
pathology [13]. However, it has long been recognised that a significant proportion of copper bound to CP is highly exchangeable [14]. One intriguing facet of CP is that reactive oxygen species including hydrogen peroxide and peroxynitritre have been shown to liberate free copper form its binding sites on CP [15,16]. It is reasonable to suggest, therefore, that an elevation of blood CP elicited by infection (and other factors) may result in an increase in HCy levels through binding of the amino acid to the copper moieties within the CP protein. In turn, the HCy associated with CP could promote the formation of reactive oxygen species and the release of copper which would further augment oxidative pathology. Further studies into this interesting area would seem to be warranted.
References [1] Khaled MA, Cornwell PE. Hyperhomoeysteinemia due to Helicobacter pylori?. Atherosclerosis 2004;172:199–200. [2] Lacy BE, Rosemore J. Helicobacter pylori: ulcers and more: the beginning of an era. J Nutr 2001;131:2789S–93S. [3] Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042–50. [4] Xu Q, Schett G, Perschinka H, et al. Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 2000;102:14–20. [5] Fox PL, Mazumder B, Ehrenwald A. Ceruloplasmin and cardiovascular disease. Free Rad Biol Med 2002;28:1735–44. [6] Dudman NPB, Wilcken DL. Increased plasma copper in patients with homocysteinuria due to cystathionine-synthase deficiency. Clin Chim Acta 1983;127:105–13. [7] Mansoor MA, Bergmark CB, Haswell SJ, et al. Correlation between plasma total homocysteine and copper in patients with peripheral vascular disease. Clin Chem 2000;46:385–91. [8] Jeremy JY, Shukla N, Angelini GD, Wan I, Talpahewa SP, Ascione R. Sustained increases in homocysteine, copper and ceruloplasmin following coronary artery bypass grafting. Ann Thorac Surg 2002;74:1553–7. [9] Daimon M, Sugiyama K, Saitoh T. Increase in serum ceruloplasmin levels is correlated with a decrease of serum nitric oxide levels in type 2 diabetes. Diab Care 2000;23:559–60. [10] Audelin MC, Genest J. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001;159:497–511. [11] Nakano E, Williamson MP, Williams NH, Powers HJ. Copper-mediated LDL oxidation by homocysteine and related compounds depends largely on copper ligation. Biochim Biophys Acta 2004;1688:33–42.
0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.04.028
202
Letter to the Editor / Atherosclerosis 176 (2004) 201–202
[12] Emsley A, Jeremy JY, Gomes G, Angelini GD, Plane F. Copper interacts with homocysteine to inhibit nitric oxide formation in the rat isolated aorta. Br J Pharmacol 1999;126:1034–40. [13] Tapiero H, Townsend DM, Tew KD. Trace elements in human physiology and pathology: copper. Biomed Pharmacother 2003;57:386–98. [14] Gutteridge JM. Copper-phenanthroline-induced site-specific oxygen-radical damage to DNA. Detection of loosely bound trace copper in biological fluids. Biochem J 1984;218:983–5. [15] Swain JA, Darley-Usmar V, Gutteridge JM. Peroxynitrite releases copper from caeruloplasmin: implications for atherosclerosis. FEBS Lett 1994;342:49–52. [16] Kim RH, Park JE, Park JW. Ceruloplasmin enhances DNA damage induced by hydrogen peroxide in vitro. Free Rad Res 2000;33:81–9.
J.Y. Jeremy∗ G.D. Angelini N. Shukla Department of Cardiac Surgery Bristol Royal Infirmary and Heart Institute University of Bristol, Bristol England BS2 7HW, UK ∗ Tel.: +44 117 928 2699 fax: +44 117 929 9737 E-mail address: [email protected] (J.Y. Jeremy) 21 April 2004
Letter to the Editor
Hyperhomocysteinemia due to Helicobacter pylori? Sir, We read with interest the letter by Khaled and Cornwell [1], who demonstrated that in subjects who were positive for Helicobacter pylori (H. pylori) there was increased plasma homocysteine (HCy) that did not appear to be due to reduced folate [1]. Given the evidence that viral and bacterial infection are associated with cadiovascular disease [2] and that HCy is an independent risk factor for CVD [3] these interrelationships have clear implications. We would like to add some comments and observations that may be of interest and relevance to this area. Firstly, infection is also associated with an elevation in the blood of the inflammation sensitive plasma proteins that include ceruloplasmin (CP) [5]. CP is a blood-borne protein that binds almost all the copper present in blood and which is itself an independent risk factor for CVD [4]. It has been known for some time that there is increased blood copper in patients with hyperhomocysteinaemia [6]. Plasma copper levels are also significantly correlated with elevated homocysteine levels in patients with peripheral arterial disease [7]. We found that following coronary artery bypass graft surgery (CABG), the blood levels of HCy and CP were increased for up to 6 weeks after surgery, indicating an association between CP, copper and HCy in the aetiology of vein graft failure [8]. Other studies have demonstrated that HCy and CP are elevated in patients with risk factors for CVD, in particular diabetes mellitus [9,10]. In a recent key study, Nakano et al. demonstrated that HCy binds avidly (chelates) copper [11]. It follows, therefore, that an increase in blood CP could result in an increase in HCy by virtue of the affinity of HCy for the copper associated with CP. In turn, this would explain why there are increased plasma levels of HCy in subjects with infection since CP is elevated in these patients. HCy and CP have been shown to interact in their own right to promote vasculopathy. For example, CP interacts with HCy through its copper moieties to promote the oxidation of low density lipoprotein [11]. Other studies have demonstrated that HCy and copper interact to generate reactive oxygen species including superoxide and hydrogen peroxide [12]. It is a widely held view that copper, due to its powerful pro-oxidant capacity, is 100% bound and as such not available for involvement in promoting oxidation-related
pathology [13]. However, it has long been recognised that a significant proportion of copper bound to CP is highly exchangeable [14]. One intriguing facet of CP is that reactive oxygen species including hydrogen peroxide and peroxynitritre have been shown to liberate free copper form its binding sites on CP [15,16]. It is reasonable to suggest, therefore, that an elevation of blood CP elicited by infection (and other factors) may result in an increase in HCy levels through binding of the amino acid to the copper moieties within the CP protein. In turn, the HCy associated with CP could promote the formation of reactive oxygen species and the release of copper which would further augment oxidative pathology. Further studies into this interesting area would seem to be warranted.
References [1] Khaled MA, Cornwell PE. Hyperhomoeysteinemia due to Helicobacter pylori?. Atherosclerosis 2004;172:199–200. [2] Lacy BE, Rosemore J. Helicobacter pylori: ulcers and more: the beginning of an era. J Nutr 2001;131:2789S–93S. [3] Welch GN, Loscalzo J. Homocysteine and atherothrombosis. N Engl J Med 1998;338:1042–50. [4] Xu Q, Schett G, Perschinka H, et al. Serum soluble heat shock protein 60 is elevated in subjects with atherosclerosis in a general population. Circulation 2000;102:14–20. [5] Fox PL, Mazumder B, Ehrenwald A. Ceruloplasmin and cardiovascular disease. Free Rad Biol Med 2002;28:1735–44. [6] Dudman NPB, Wilcken DL. Increased plasma copper in patients with homocysteinuria due to cystathionine-synthase deficiency. Clin Chim Acta 1983;127:105–13. [7] Mansoor MA, Bergmark CB, Haswell SJ, et al. Correlation between plasma total homocysteine and copper in patients with peripheral vascular disease. Clin Chem 2000;46:385–91. [8] Jeremy JY, Shukla N, Angelini GD, Wan I, Talpahewa SP, Ascione R. Sustained increases in homocysteine, copper and ceruloplasmin following coronary artery bypass grafting. Ann Thorac Surg 2002;74:1553–7. [9] Daimon M, Sugiyama K, Saitoh T. Increase in serum ceruloplasmin levels is correlated with a decrease of serum nitric oxide levels in type 2 diabetes. Diab Care 2000;23:559–60. [10] Audelin MC, Genest J. Homocysteine and cardiovascular disease in diabetes mellitus. Atherosclerosis 2001;159:497–511. [11] Nakano E, Williamson MP, Williams NH, Powers HJ. Copper-mediated LDL oxidation by homocysteine and related compounds depends largely on copper ligation. Biochim Biophys Acta 2004;1688:33–42.
0021-9150/$ – see front matter © 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2004.04.028
202
Letter to the Editor / Atherosclerosis 176 (2004) 201–202
[12] Emsley A, Jeremy JY, Gomes G, Angelini GD, Plane F. Copper interacts with homocysteine to inhibit nitric oxide formation in the rat isolated aorta. Br J Pharmacol 1999;126:1034–40. [13] Tapiero H, Townsend DM, Tew KD. Trace elements in human physiology and pathology: copper. Biomed Pharmacother 2003;57:386–98. [14] Gutteridge JM. Copper-phenanthroline-induced site-specific oxygen-radical damage to DNA. Detection of loosely bound trace copper in biological fluids. Biochem J 1984;218:983–5. [15] Swain JA, Darley-Usmar V, Gutteridge JM. Peroxynitrite releases copper from caeruloplasmin: implications for atherosclerosis. FEBS Lett 1994;342:49–52. [16] Kim RH, Park JE, Park JW. Ceruloplasmin enhances DNA damage induced by hydrogen peroxide in vitro. Free Rad Res 2000;33:81–9.
J.Y. Jeremy∗ G.D. Angelini N. Shukla Department of Cardiac Surgery Bristol Royal Infirmary and Heart Institute University of Bristol, Bristol England BS2 7HW, UK ∗ Tel.: +44 117 928 2699 fax: +44 117 929 9737 E-mail address: [email protected] (J.Y. Jeremy) 21 April 2004