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Diabetes and chronic nitrate therapy as co-determinants of somatic DNA damage in patients with coronary artery disease

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Abstract

Somatic DNA damage has been linked to coronary artery disease (CAD). However, whether genetic instability is linked to CAD per se or to concomitant potentially genotoxic metabolic and pharmacological factors remains still unclear. The aim of this study was to evaluate the determinants of somatic DNA damage in a large population of patients undergoing coronary angiography. A total of 278 in-hospital patients (215 men, age 61.8±0.7 years) were studied by using micronucleus assay (MN) in human lymphocytes, which is one of the most commonly used biomarker for somatic DNA damage. Significant CAD (>50% diameter stenosis) was present in 210 patients (179 men, age 62.3±0.7 years). Normal coronary arteries were observed in 68 patients (35 men, age 60.2±1.7 years). There were no significant differences between patients with and without CAD, but patients with multivessel disease had the highest MN levels (P=0.01). MN frequency was also found significantly higher in presence of type 2 diabetes (P<0.0001), dyslipidemia (P=0.048) and nitrate therapy (P=0.0002). A significant additive effect was also observed between diabetes and nitrate therapy (P=0.02). On multivariate logistic regression analysis, diabetes [odds ratio =6.8 (95% confidence interval, 3.2–14.5), P<0.0001] and nitrate therapy [odds ratio =2.4 (95% confidence interval, 1.3–4.7), P=0.01] remained the only significant determinants for the 50th percentile of MN (>12‰). These results indicated that diabetes and, to a lesser extent, chronic nitrate therapy are major determinants of somatic DNA instability in patients with CAD. DNA damage might represent an additional pathogenetic dimension and a possible therapeutic target in the still challenging management of coronary artery disease concerning diabetics.

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References

  1. Adams J, Apple F (2004) Cardiology patient page. New blood tests for detecting heart disease. Circulation 109:E12–E14

    Google Scholar 

  2. De Flora S, Izzotti A, Randerath K, et al (1996) DNA adducts and chronic degenerative disease. Pathogenetic relevance and implications in preventive medicine. Mutat Res 366:197–238

    Google Scholar 

  3. Migliore L, Coppede F (2002) Genetic and environmental factors in cancer and neurodegenerative diseases. Mutat Res 512:135–153

    Google Scholar 

  4. Izzotti (2003) DNA damage and alterations of gene expression in chronic-degenerative diseases. Acta Biochim Pol 50:145–154

    Google Scholar 

  5. Andreassi MG (2003) Coronary atherosclerosis and somatic mutations: an overview of the contributive factors for oxidative DNA damage. Mutat Res 543:67–86

    Google Scholar 

  6. Cooke MS, Evans MD, Dizdaroglu M, et al (2003) Oxidative DNA damage: mechanisms, mutation, and disease. FASEB J 17:1195–1214

    Article  CAS  PubMed  Google Scholar 

  7. Casella M, Lucarelli M, Simili M, et al (2003) Spontaneous chromosome loss and colcemid resistance in lymphocytes from patients with myotonic dystrophy type 1. Cytogenet Genome Res 100:224–229

    Google Scholar 

  8. Botto N, Masetti S, Petrozzi L, et al (2002) Elevated levels of oxidative DNA damage in patients with coronary artery disease. Coron Artery Dis 13:269–274

    Google Scholar 

  9. Andreassi MG, Botto N, Rizza A, et al (2001) Chronic long-term nitrate therapy: possible cytogenetic effect in humans? Mutagenesis 16:517–521

    Google Scholar 

  10. Andreassi MG, Botto N, Rizza A, et al (2002) Deoxyribonucleic acid damage in human lymphocytes after percutaneous transluminal coronary angioplasty. J Am Coll Cardiol 40:862–868

    Google Scholar 

  11. Fenech M (1993) The cytokinesis-block micronucleus technique and its application to genotoxicity studies in human populations. Environ Health Perspect 101:101–107

    Google Scholar 

  12. Fenech M (2002) Biomarkers of genetic damage for cancer epidemiology. Toxicology 181–182:411–416

    Google Scholar 

  13. Barale R, Chelotti L, Davini T, et al (1998) Sister chromatid exchange and micronucleus frequency in human lymphocytes of 1,650 subjects in an Italian population: II. Contribution of sex, age, and lifestyle. Environ Mol Mutagen 31:228–242

    Google Scholar 

  14. Bonassi S, Fenech M, Lando C, et al (2001) Human MicroNucleus project: international database comparison for results with the cytokinesis-block micronucleus assay in human lymphocytes: I. Effect of laboratory protocol, scoring criteria, and host factors on the frequency of micronuclei. Environ Mol Mutagen 37:31–45

    Google Scholar 

  15. Olinski R, Gackowski D, Foksinski M, et al (2002) Oxidative DNA damage: assessment of the role in carcinogenesis, atherosclerosis, and acquired immunodeficiency syndrome. Free Radic Biol Med 33:192–200

    Google Scholar 

  16. Baynes JW, Thorpe SR (1999) Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48:1–9

    CAS  PubMed  Google Scholar 

  17. Jialal I, Devaraj S, Venugopal SK (2002) Oxidative stress, inflammation, and diabetic vasculopathies: the role of alpha tocopherol therapy. Free Radic Res 36:1331–1336

    Google Scholar 

  18. Dandona P, Thusu K, Cook S, et al (1996) Oxidative damage to DNA in diabetes mellitus. Lancet 347444–347445

  19. Collins AR, Raslova K, Somorovska M, et al (1998) DNA damage in diabetes: correlation with a clinical marker. Free Radic Biol Med 25:373–377

    Google Scholar 

  20. Hinokio Y, Suzuki S, Hirai M, et al (1999) Oxidative DNA damage in diabetes mellitus: its association with diabetic complications. Diabetologia 42:995–998

    Google Scholar 

  21. Hannon-Fletcher MP, O’Kane MJ, Moles KW, et al (2000) Levels of peripheral blood cell DNA damage in insulin dependent diabetes mellitus human subjects. Mutat Res 460:53–60

    Google Scholar 

  22. Sardas S, Yilmaz M, Oztok U, et al (2001) Assessment of DNA strand breakage by comet assay in diabetic patients and the role of antioxidant supplementation. Mutat Res 490:123–129

    Google Scholar 

  23. Shin CS, Moon BS, Park KS, et al (2001) Serum 8-hydroxy-guanine levels are increased in diabetic patients. Diabetes Care 24:733–737

    Google Scholar 

  24. Dincer Y, Akcay T, Ilkova H, et al (2003) DNA damage and antioxidant defense in peripheral leukocytes of patients with type I diabetes mellitus. Mutat Res 527:49–55

    Google Scholar 

  25. Moochhala S, Rajnakova A (1999) Role of nitric oxide in cancer biology. Free Radic Res 31:671–679

    Google Scholar 

  26. Felley-Bosco E (1998) Role of nitric oxide in genotoxicity: implication for carcinogenesis. Cancer Metastasis Rev 17:25–37

    Google Scholar 

  27. Burney S, Caulfield J, Niles J, et al (1999) The chemistry of DNA damage from nitric oxide and peroxynitrite. Mutat Res 424:37–49

    Article  CAS  PubMed  Google Scholar 

  28. Nakamura Y, Moss AJ, Brown MW, et al (1999) Long-term nitrate use may be deleterious in ischemic heart disease: a study using the databases from two large-scale postinfarction studies. Am Heart J 138:577–585

    Google Scholar 

  29. Kanamasa K, Hayashi T, Kimura A, et al (2002) Long-term, continuous treatment with both oral and transdermal nitrates increases cardiac events in healed myocardial infarction patients. Angiology 53:399–340

    Google Scholar 

  30. Nesto RW, Libby P (2001) Diabetes mellitus abd the cardiovascular system. In: Braunwald E, Zipes DP, Libby P (eds). Heart disease. A textbook of cardiovascular medicine, 6th edn. WB Saunders, Philadelphia, pp 2133–2150

    Google Scholar 

  31. Garcia Soriano F, Virag L, Jagtap P, et al (2001) Diabetic endothelial dysfunction: the role of poly(ADP-ribose) polymerase activation. Nat Med 7:108–113

    Google Scholar 

  32. Garcia Soriano F, Pacher P, Mabley J, Liaudet L, Szabo C (2001) Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly(ADP-ribose) polymerase. Circ Res 89:684–691

    Google Scholar 

  33. Pacher P, Liaudet L, Soriano FG, Mabley JG, Szabo E, Szabo C (2002) The role of poly(ADP-ribose) polymerase activation in the development of myocardial and endothelial dysfunction in diabetes. Diabetes 51:514–521

    Google Scholar 

  34. Garcia Soriano F, Virag L, Szabo C (2001) Diabetic endothelial dysfunction: role of reactive oxygen and nitrogen species production and poly (ADP-ribose) polymerase activation. J Mol Med 79:437–448

    Google Scholar 

  35. Virag L, Szabo E, Gergely P, Szabo C (2003) Peroxynitrite-induced cytotoxicity: mechanism and opportunities for intervention. Toxicol Lett 140–141:113–124

    Google Scholar 

  36. Szabo C (2002) PARP as a drug target for the therapy of diabetic cardiovascular dysfunction. Drug News Perspect 15:197–205

    Google Scholar 

  37. Miller MC III, Mohrenweiser HW, Bell DA (2001) Genetic variability in susceptibility and response to toxicants. Toxicol Lett 120:269–280

    Google Scholar 

  38. Picano E (2003) Stress echocardiography: a historical perspective. Am J Med 114:126–130

    Google Scholar 

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Authors and Affiliations

  1. CNR Institute of Clinical Physiology, Pisa, Italy

    Maria Grazia Andreassi, Nicoletta Botto, Silvana Simi, Marta Casella, Samantha Manfredi, Marilena Lucarelli, Lucia Venneri, Andrea Biagini & Eugenio Picano

  2. CNR Institute of Clinical Physiology, G. Pasquinucci Hospital, Via Aurelia Sud-Montepepe, 54100, Massa, Italy

    Maria Grazia Andreassi

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  1. Maria Grazia Andreassi
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  2. Nicoletta Botto
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  3. Silvana Simi
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  4. Marta Casella
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  5. Samantha Manfredi
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  6. Marilena Lucarelli
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  7. Lucia Venneri
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  8. Andrea Biagini
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  9. Eugenio Picano
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Correspondence to Maria Grazia Andreassi.

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Andreassi, M.G., Botto, N., Simi, S. et al. Diabetes and chronic nitrate therapy as co-determinants of somatic DNA damage in patients with coronary artery disease. J Mol Med 83, 279–286 (2005). https://doi.org/10.1007/s00109-005-0634-8

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  • DOI: https://doi.org/10.1007/s00109-005-0634-8

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