Skip to main content
SpringerLink
Log in

Endogenous nitric oxide formation correlates negatively with circulating matrix metalloproteinase (MMP)-2 and MMP-9 levels in black subjects

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Deficient formation of endogenous nitric oxide (NO) contributes to cardiovascular diseases, and this may be associated with increased circulating levels of matrix metalloproteinase-9 (MMP-9), as previously shown in white subjects. Because interethnic differences exist with respect to risk factors, prevalence, and severity of cardiovascular diseases, we designed this study to examine whether the circulating levels of nitrites (a marker of endogenous NO formation) are associated with the plasma levels of MMP-9 and MMP-2 in healthy black subjects. We studied 198 healthy subjects self-reported as blacks not taking any medications. Venous blood samples were collected and plasma and whole blood nitrite levels were measured using an ozone-based chemiluminescence assay. Plasma MMP-2 and MMP-9 levels were determined by gelatin zymography. We found a positive correlation between plasma MMP-9 and MMP-2 levels (P < 0.0001, rs = 0.556). Interestingly, we found a negative relationship between the plasma MMP-9 levels and the plasma or whole blood nitrites levels (P = 0.04, rs = −0.149; and P < 0.0001, rs = −0.349, respectively). In parallel, we found similar negative relationships between plasma MMP-2 levels and plasma or whole blood nitrites levels (P = 0.02, rs = −0.172; and P < 0.0001, rs = −0.454, respectively). This is the first study to show that endogenous nitric oxide formation correlates negatively with the circulating levels of both MMP-2 and MMP-9 in black subjects. Our findings suggest a mechanistic link between deficient NO formation and increased MMPs levels, which may promote cardiovascular diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Moncada S, Higgs EA (1991) Endogenous nitric oxide: physiology, pathology and clinical relevance. Eur J Clin Invest 21(4):361–374

    Article  PubMed  CAS  Google Scholar 

  2. Castro MM, Rizzi E, Figueiredo-Lopes L, Fernandes K, Bendhack LM, Pitol DL, Gerlach RF, Tanus-Santos JE (2008) Metalloproteinase inhibition ameliorates hypertension and prevents vascular dysfunction and remodeling in renovascular hypertensive rats. Atherosclerosis 198(2):320–331

    Article  PubMed  CAS  Google Scholar 

  3. Castro MM, Rizzi E, Prado CM, Rossi MA, Tanus-Santos JE, Gerlach RF (2010) Imbalance between matrix metalloproteinases and tissue inhibitor of metalloproteinases in hypertensive vascular remodeling. Matrix Biol 29(3):194–201

    Article  PubMed  CAS  Google Scholar 

  4. Lacchini R, Jacob-Ferreira AL, Luizon MR, Coeli FB, Izidoro-Toledo TC, Gasparini S, Ferreira-Sae MC, Schreiber R, Nadruz W Jr, Tanus-Santos JE (2010) Matrix metalloproteinase 9 gene haplotypes affect left ventricular hypertrophy in hypertensive patients. Clin Chim Acta 411:1940–1944

    Article  PubMed  CAS  Google Scholar 

  5. Rizzi E, Castro MM, Prado CM, Silva CA, Fazan R Jr, Rossi MA, Tanus-Santos JE, Gerlach RF (2010) Matrix metalloproteinase inhibition improves cardiac dysfunction and remodeling in 2-kidney, 1-clip hypertension. J Card Fail 16(7):599–608

    Article  PubMed  CAS  Google Scholar 

  6. Belo VA, Souza-Costa DC, Lana CM, Caputo FL, Marcaccini AM, Gerlach RF, Bastos MG, Tanus-Santos JE (2009) Assessment of matrix metalloproteinase (MMP)-2, MMP-8, MMP-9, and their inhibitors, the tissue inhibitors of metalloproteinase (TIMP)-1 and TIMP-2 in obese children and adolescents. Clin Biochem 42(10–11):984–990

    Article  PubMed  CAS  Google Scholar 

  7. Goncalves FM, Jacob-Ferreira AL, Gomes VA, Casella-Filho A, Chagas AC, Marcaccini AM, Gerlach RF, Tanus-Santos JE (2009) Increased circulating levels of matrix metalloproteinase (MMP)-8, MMP-9, and pro-inflammatory markers in patients with metabolic syndrome. Clin Chim Acta 403(1–2):173–177

    Article  PubMed  CAS  Google Scholar 

  8. Martinez ML, Rizzi E, Castro MM, Fernandes K, Bendhack LM, Gerlach RF, Tanus-Santos JE (2008) Lercanidipine decreases vascular matrix metalloproteinase-2 activity and protects against vascular dysfunction in diabetic rats. Eur J Pharmacol 599(1–3):110–116

    Article  PubMed  CAS  Google Scholar 

  9. Fontana V, Silva PS, Belo VA, Antonio RC, Ceron CS, Biagi C, Gerlach RF, Tanus-Santos JE (2011) Consistent alterations of circulating matrix metalloproteinases levels in untreated hypertensives and in spontaneously hypertensive rats: a relevant pharmacological target. Basic Clin Pharmacol Toxicol 109(2):130–137

    Article  PubMed  CAS  Google Scholar 

  10. Demacq C, Metzger IF, Gerlach RF, Tanus-Santos JE (2008) Inverse relationship between markers of nitric oxide formation and plasma matrix metalloproteinase-9 levels in healthy volunteers. Clin Chim Acta 394(1–2):72–76

    Article  PubMed  CAS  Google Scholar 

  11. Eagleton MJ, Peterson DA, Sullivan VV, Roelofs KJ, Ford JA, Stanley JC, Upchurch GR Jr (2002) Nitric oxide inhibition increases aortic wall matrix metalloproteinase-9 expression. J Surg Res 104(1):15–21

    Article  PubMed  CAS  Google Scholar 

  12. Upchurch GR Jr, Ford JW, Weiss SJ, Knipp BS, Peterson DA, Thompson RW, Eagleton MJ, Broady AJ, Proctor MC, Stanley JC (2001) Nitric oxide inhibition increases matrix metalloproteinase-9 expression by rat aortic smooth muscle cells in vitro. J Vasc Surg 34(1):76–83

    Article  PubMed  Google Scholar 

  13. Gurjar MV, DeLeon J, Sharma RV, Bhalla RC (2001) Mechanism of inhibition of matrix metalloproteinase-9 induction by NO in vascular smooth muscle cells. J Appl Physiol 91(3):1380–1386

    PubMed  CAS  Google Scholar 

  14. Gladwin MT, Raat NJ, Shiva S, Dezfulian C, Hogg N, Kim-Shapiro DB, Patel RP (2006) Nitrite as a vascular endocrine nitric oxide reservoir that contributes to hypoxic signaling, cytoprotection, and vasodilation. Am J Physiol Heart Circ Physiol 291(5):H2026–H2035

    Article  PubMed  CAS  Google Scholar 

  15. Gladwin MT, Crawford JH, Patel RP (2004) The biochemistry of nitric oxide, nitrite, and hemoglobin: role in blood flow regulation. Free Radic Biol Med 36(6):707–717

    Article  PubMed  CAS  Google Scholar 

  16. Webb A, Bond R, McLean P, Uppal R, Benjamin N, Ahluwalia A (2004) Reduction of nitrite to nitric oxide during ischemia protects against myocardial ischemia-reperfusion damage. Proc Natl Acad Sci USA 101(37):13683–13688

    Article  PubMed  CAS  Google Scholar 

  17. Kleinbongard P, Dejam A, Lauer T, Jax T, Kerber S, Gharini P, Balzer J, Zotz RB, Scharf RE, Willers R, Schechter AN, Feelisch M, Kelm M (2006) Plasma nitrite concentrations reflect the degree of endothelial dysfunction in humans. Free Radic Biol Med 40(2):295–302

    Article  PubMed  CAS  Google Scholar 

  18. Metzger IF, Sertorio JT, Tanus-Santos JE (2006) Relationship between systemic nitric oxide metabolites and cyclic GMP in healthy male volunteers. Acta Physiol (Oxf) 188(2):123–127

    Article  CAS  Google Scholar 

  19. Murphy C, Kanaganayagam GS, Jiang B, Chowienczyk PJ, Zbinden R, Saha M, Rahman S, Shah AM, Marber MS, Kearney MT (2007) Vascular dysfunction and reduced circulating endothelial progenitor cells in young healthy UK South Asian men. Arterioscler Thromb Vasc Biol 27(4):936–942

    Article  PubMed  CAS  Google Scholar 

  20. Rosenbaum DA, Pretorius M, Gainer JV, Byrne D, Murphey LJ, Painter CA, Vaughan DE, Brown NJ (2002) Ethnicity affects vasodilation, but not endothelial tissue plasminogen activator release, in response to bradykinin. Arterioscler Thromb Vasc Biol 22(6):1023–1028

    Article  PubMed  CAS  Google Scholar 

  21. Fenster CP, Darley-Usmar VM, Landar AL, Gower BA, Weinsier RL, Hunter GR, Patel RP (2004) Weight loss and race modulate nitric oxide metabolism in overweight women. Free Radic Biol Med 37(5):695–702

    Article  PubMed  CAS  Google Scholar 

  22. Ke RW, Todd Pace D, Ahokas RA (2003) Effect of short-term hormone therapy on oxidative stress and endothelial function in African American and Caucasian postmenopausal women. Fertil Steril 79(5):1118–1122

    Article  PubMed  Google Scholar 

  23. Stein CM, Lang CC, Nelson R, Brown M, Wood AJ (1997) Vasodilation in black Americans: attenuated nitric oxide-mediated responses. Clin Pharmacol Ther 62(4):436–443

    Article  PubMed  CAS  Google Scholar 

  24. Sareli P, Radevski IV, Valtchanova ZP, Libhaber E, Candy GP, Den Hond E, Libhaber C, Skudicky D, Wang JG, Staessen JA (2001) Efficacy of different drug classes used to initiate antihypertensive treatment in black subjects: results of a randomized trial in Johannesburg, South Africa. Arch Intern Med 161(7):965–971

    Article  PubMed  CAS  Google Scholar 

  25. Kalinowski L, Dobrucki IT, Malinski T (2004) Race-specific differences in endothelial function: predisposition of African Americans to vascular diseases. Circulation 109(21):2511–2517

    Article  PubMed  Google Scholar 

  26. Fielitz J, Leuschner M, Zurbrugg HR, Hannack B, Pregla R, Hetzer R, Regitz-Zagrosek V (2004) Regulation of matrix metalloproteinases and their inhibitors in the left ventricular myocardium of patients with aortic stenosis. J Mol Med 82(12):809–820

    Article  PubMed  CAS  Google Scholar 

  27. Marroni AS, Metzger IF, Souza-Costa DC, Nagassaki S, Sandrim VC, Correa RX, Rios-Santos F, Tanus-Santos JE (2005) Consistent interethnic differences in the distribution of clinically relevant endothelial nitric oxide synthase genetic polymorphisms. Nitric Oxide 12(3):177–182

    Article  PubMed  CAS  Google Scholar 

  28. Tanus-Santos JE, Desai M, Flockhart DA (2001) Effects of ethnicity on the distribution of clinically relevant endothelial nitric oxide variants. Pharmacogenetics 11(8):719–725

    Article  PubMed  CAS  Google Scholar 

  29. Lacchini R, Metzger IF, Luizon M, Ishizawa M, Tanus-Santos JE (2010) Interethnic differences in the distribution of matrix metalloproteinases genetic polymorphisms are consistent with interethnic differences in disease prevalence. DNA Cell Biol 29(11):649–655

    Article  PubMed  CAS  Google Scholar 

  30. Bibbins-Domingo K, Pletcher MJ, Lin F, Vittinghoff E, Gardin JM, Arynchyn A, Lewis CE, Williams OD, Hulley SB (2009) Racial differences in incident heart failure among young adults. N Engl J Med 360(12):1179–1190

    Article  PubMed  CAS  Google Scholar 

  31. Bahrami H, Kronmal R, Bluemke DA, Olson J, Shea S, Liu K, Burke GL, Lima JA (2008) Differences in the incidence of congestive heart failure by ethnicity: the multi-ethnic study of atherosclerosis. Arch Intern Med 168(19):2138–2145

    Article  PubMed  Google Scholar 

  32. Mensah GA, Mokdad AH, Ford ES, Greenlund KJ, Croft JB (2005) State of disparities in cardiovascular health in the United States. Circulation 111(10):1233–1241

    Article  PubMed  Google Scholar 

  33. Hozawa A, Folsom AR, Sharrett AR, Chambless LE (2007) Absolute and attributable risks of cardiovascular disease incidence in relation to optimal and borderline risk factors: comparison of African American with white subjects–Atherosclerosis Risk in Communities Study. Arch Intern Med 167(6):573–579

    Article  PubMed  Google Scholar 

  34. Carroll JF, Fulda KG, Chiapa AL, Rodriquez M, Phelps DR, Cardarelli KM, Vishwanatha JK, Cardarelli R (2009) Impact of race/ethnicity on the relationship between visceral fat and inflammatory biomarkers. Obesity (Silver Spring) 17(7):1420–1427

    CAS  Google Scholar 

  35. Nagassaki S, Sertorio JT, Metzger IF, Bem AF, Rocha JB, Tanus-Santos JE (2006) eNOS gene T-786C polymorphism modulates atorvastatin-induced increase in blood nitrite. Free Radic Biol Med 41(7):1044–1049

    Article  PubMed  CAS  Google Scholar 

  36. Demacq C, Vasconcellos VB, Marcaccini AM, Gerlach RF, Silva WA, Tanus-Santos JE (2008) Functional polymorphisms in the promoter of the matrix metalloproteinase-9 (MMP-9) gene are not linked with significant plasma MMP-9 variations in healthy subjects. Clin Chem Lab Med 46(1):57–63

    Article  PubMed  CAS  Google Scholar 

  37. Gerlach RF, Demacq C, Jung K, Tanus-Santos JE (2007) Rapid separation of serum does not avoid artificially higher matrix metalloproteinase (MMP)-9 levels in serum versus plasma. Clin Biochem 40(1–2):119–123

    Article  PubMed  CAS  Google Scholar 

  38. Akool el S, Kleinert H, Hamada FM, Abdelwahab MH, Forstermann U, Pfeilschifter J, Eberhardt W (2003) Nitric oxide increases the decay of matrix metalloproteinase 9 mRNA by inhibiting the expression of mRNA-stabilizing factor HuR. Mol Cell Biol 23(14):4901–4916

    Article  Google Scholar 

  39. Eberhardt W, Beeg T, Beck KF, Walpen S, Gauer S, Bohles H, Pfeilschifter J (2000) Nitric oxide modulates expression of matrix metalloproteinase-9 in rat mesangial cells. Kidney Int 57(1):59–69

    Article  PubMed  CAS  Google Scholar 

  40. Montenegro MF, Amaral JH, Pinheiro LC, Sakamoto EK, Ferreira GC, Reis RI, Marcal DM, Pereira RP, Tanus-Santos JE (2011) Sodium nitrite downregulates vascular NADPH oxidase and exerts antihypertensive effects in hypertension. Free Radic Biol Med 51(1):144–152

    Article  PubMed  CAS  Google Scholar 

  41. Dias-Junior CA, Cau SB, Oliveira AM, Castro MM, Montenegro MF, Gerlach RF, Tanus-Santos JE (2009) Nitrite or sildenafil, but not BAY 41–2272, blunt acute pulmonary embolism-induced increases in circulating matrix metalloproteinase-9 and oxidative stress. Thromb Res 124(3):349–355

    Article  PubMed  CAS  Google Scholar 

  42. Dias-Junior CA, Gladwin MT, Tanus-Santos JE (2006) Low-dose intravenous nitrite improves hemodynamics in a canine model of acute pulmonary thromboembolism. Free Radic Biol Med 41(12):1764–1770

    Article  PubMed  CAS  Google Scholar 

  43. Metzger IF, Ishizawa MH, Rios-Santos F, Carvalho WA, Tanus-Santos JE (2011) Endothelial nitric oxide synthase gene haplotypes affect nitrite levels in black subjects. Pharmacogenomics J. doi:10.1038/tpj.2010.52

  44. Dejam A, Hunter CJ, Pelletier MM, Hsu LL, Machado RF, Shiva S, Power GG, Kelm M, Gladwin MT, Schechter AN (2005) Erythrocytes are the major intravascular storage sites of nitrite in human blood. Blood 106(2):734–739

    Article  PubMed  CAS  Google Scholar 

  45. Kehmeier ES, Kropp M, Kleinbongard P, Lauer T, Balzer J, Merx MW, Heusch G, Kelm M, Lepper W, Rassaf T (2008) Serial measurements of whole blood nitrite in an intensive care setting. Free Radic Biol Med 44(11):1945–1950

    Article  PubMed  CAS  Google Scholar 

  46. Souza-Costa DC, Figueiredo-Lopes L, Alves-Filho JC, Semprini MC, Gerlach RF, Cunha FQ, Tanus-Santos JE (2007) Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9. Crit Care Med 35(1):239–245

    Article  PubMed  CAS  Google Scholar 

  47. Souza-Costa DC, Sandrim VC, Lopes LF, Gerlach RF, Rego EM, Tanus-Santos JE (2007) Anti-inflammatory effects of atorvastatin: modulation by the T-786C polymorphism in the endothelial nitric oxide synthase gene. Atherosclerosis 193(2):438–444

    Article  PubMed  CAS  Google Scholar 

  48. Barbosa F Jr, Sertorio JT, Gerlach RF, Tanus-Santos JE (2006) Clinical evidence for lead-induced inhibition of nitric oxide formation. Arch Toxicol 80(12):811–816

    Article  PubMed  CAS  Google Scholar 

  49. de Marco KC, Passos CJ, Sertorio J, Tanus-Santos JE, Barbosa F Jr (2010) Environmental exposure to methylmercury is associated with a decrease in nitric oxide production. Basic Clin Pharmacol Toxicol 106(5):411–415

    PubMed  Google Scholar 

  50. Barbosa F Jr, Gerlach RF, Tanus-Santos JE (2006) Matrix metalloproteinase-9 activity in plasma correlates with plasma and whole blood lead concentrations. Basic Clin Pharmacol Toxicol 98(6):559–564

    Article  PubMed  CAS  Google Scholar 

  51. Jacob-Ferreira AL, Passos CJ, Jordao AA, Fillion M, Mergler D, Lemire M, Gerlach RF, Barbosa Jr F, Tanus-Santos JE (2009) Mercury Exposure Increases Circulating Net Matrix Metalloproteinase (MMP)-2 and MMP-9 Activities. Basic Clin Pharmacol Toxicol 105:281–288

    Google Scholar 

Download references

Acknowledgment

This study was supported by Fundação de Amparo à Pesquisa do Estado de Sao Paulo, Conselho Nacional de Desenvolvimento Científico e Tecnologico and Coordenadoria de Aperfeiçoamento de Pessoal de Nível Superior.

Author information

Authors and Affiliations

  1. Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900, SP, Ribeirao Preto, Brazil

    Ingrid F. Metzger & Jose E. Tanus-Santos

  2. Santa Casa de Belo Horizonte, Núcleo de Pós-Graduação, MG, Belo Horizonte, Brazil

    Valéria C. Sandrim

Authors
  1. Ingrid F. Metzger
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valéria C. Sandrim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jose E. Tanus-Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jose E. Tanus-Santos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Metzger, I.F., Sandrim, V.C. & Tanus-Santos, J.E. Endogenous nitric oxide formation correlates negatively with circulating matrix metalloproteinase (MMP)-2 and MMP-9 levels in black subjects. Mol Cell Biochem 360, 393–399 (2012). https://doi.org/10.1007/s11010-011-1079-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-011-1079-8

Keywords

Search

Navigation