Skip to main content
SpringerLink
Log in

Matrix imbalance by inducing expression of metalloproteinase and oxidative stress in cochlea of hyperhomocysteinemic mice

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

Abstract

Clinical study reports hearing loss in patients with low folic acid (FA) and elevated homocysteine (Hcy). We hypothesize that elevated Hcy induces imbalance in matrix turnover and oxidative stress in cochlea. Cystathione β-synthase heterozygous knockout mice were used as model for hyperhomocysteinemia. Matrix remodeling induced by Hcy resulted from elevated MMP-2, -9, and -14. MMP-2 and -9 showed elevated gelatinase activity in CBS (+/−) cochlea. Tissue inhibitors of matrix metalloproteinase were significantly lower in CBS (+/−) cochlea. The expression analyses for MMPs and TIMPs were equally represented at protein and mRNA levels. Cochlea of CBS mice showed following structural changes; (1) detachment of tectorial membrane lying on hair cells (2) thinner s. vascularis (3) large fibroblast in spiral ligament. Hcy induced higher protein nitrotyrosination and cytosolic NADPHoxidase subunit p22phox in cochlea. It is thus suggested that Hcy induced matrix imbalance, structural changes and oxidative stress in cochlea.

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
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Abbreviations

CBS:

Cystathione-beta synthase

MMP:

Matrix metalloproteinase

TIMP:

Tissue inhibitors of matrix metalloproteinase

Hcy:

Homocysteine

References

  1. Berner B, Odum L, Parving A (2000) Age-related hearing impairment and B-vitamin status. Acta Otolaryngol 120:633–637

    Article  PubMed  CAS  Google Scholar 

  2. Cadoni G, Agostino S, Scipione S et al (2004) Low serum folate levels: a risk factor for sudden sensorineural hearing loss? Acta Otolaryngol 124(5):608–611

    Article  PubMed  CAS  Google Scholar 

  3. Durga J, Verhoef P, Anteunis LJC et al (2007) Effects of folic acid supplementation on hearing in older adults: a randomized, controlled trial. Ann Intern Med 146(1):1–8

    PubMed  Google Scholar 

  4. Fattori B, Nacci A, Casani A et al (2001) Hemostatic alterations in patients with acute, unilateral vestibular paresis. Otolaryngol Head Neck Surg 124:401–407

    Article  PubMed  CAS  Google Scholar 

  5. Graham IM, Daly LE, Refsum HM et al (1997) Plasma homocysteine as a risk factor for vascular disease: the European concerted action project. JAMA 277:1775–1781

    Article  PubMed  CAS  Google Scholar 

  6. Bautista LE, Arenas IA, Penuela A, Martinez LX (2002) Total plasma homocysteine level and risk of cardiovascular disease: a meta-analysis of prospective cohort studies. J Clin Epidemiol 55:882–887

    Article  PubMed  Google Scholar 

  7. Weiss N, Heydrick SJ, Postea O, Keller C, Keaney JF Jr, Loscalz J (2003) Influence of hyperhomocysteinemia on the cellular redox state: impact on homocysteine-induced endothelial dysfunction. Clin Chem Lab Med 41(11):1455–1461

    Article  PubMed  CAS  Google Scholar 

  8. Papatheodorou L, Weiss N (2007) Vascular oxidant stress and inflammation in hyperhomocysteinemia. Antioxid Redox Signal 9:1941–1958

    Article  PubMed  CAS  Google Scholar 

  9. Durga J, Anteunis LJC, Schouten EG et al (2006) Association of folate with hearing is dependet on the 5, 10-methylenetetrahydro folate reductse 677C-T mutation. Neurobiol Aging 27(3):482–489

    Article  PubMed  CAS  Google Scholar 

  10. Cohen-Salmon M, Regnault B, Cayet N et al (2007) Connexin30 deficiency causes instrastrial fluid-blood barrier disruption within the cochlear stria vascularis. Proc Natl Acad Sci USA 104(15):6229–6234

    Article  PubMed  CAS  Google Scholar 

  11. Meyer zum Gottesberge AM, Gross O, Becker-Lendzian U, Massing T, Vogel WF (2008) Inner ear defects and hearing loss in mice lacking the collagen receptor DDR1. Lab Invest 88(1):27–37

    Article  PubMed  CAS  Google Scholar 

  12. Kundu S, Kumar M, Sen U et al (2009) Nitrotyrosinylation, remodeling and endothelial-myocyte uncoupling in iNOS, cystathionine beta synthase (CBS) knockouts and iNOS/CBS double knockout mice. J Cell Biochem 106(1):119–126

    Article  PubMed  CAS  Google Scholar 

  13. Sen U, Moshal KS, Singh M et al (2007) Homocysteine induced biochemical stress predisposes to cytoskeletal remodeling in strechd endothelial cells. Mol Cell Biochem 302(1–2):133–143

    Article  PubMed  CAS  Google Scholar 

  14. Kumar M, Tyagi N, Moshal KS (2008) Homocysteine decreases blood flow to the brain due to vascular resistance in carotid artery. Neurochem Int 53(6–8):214–219

    Article  PubMed  CAS  Google Scholar 

  15. Kumar M, Tyagi N, Moshal KS et al (2008) GABAA receptor agonist mitigates homocysteine-induced cerebrovascular remodeling in knockout mice. Brain Res 1221:147–153

    Article  PubMed  CAS  Google Scholar 

  16. Wang L, Jhee KH, Hua X, DiBello PM, Jacobsen DW, Kruger WD (2004) Modulation of cystathionine beta-synthase level regulates total serum homocysteine in mice. Circ Res 94:1318–1324

    Article  PubMed  CAS  Google Scholar 

  17. Jhee KH, Kruger WD (2005) The role of cystathionine beta-synthase in homocysteine metabolism. Antioxid Redox Signal 7:813–822

    Article  PubMed  CAS  Google Scholar 

  18. Watanabe M, Osada J, Aratani Y et al (1995) Mice deficient in cystathionine beta-synthase: animal models for mild and severe homocyst(e)inemia. Proc Natl Acad Sci USA 92:1585–1589

    Article  PubMed  CAS  Google Scholar 

  19. Eberhardt RT, Forgione MA, Cap A et al (2000) Endothelial dysfunction in a murine model of mild hyperhomocyst(e)inemia. J Clin Invest 106:483–491

    Article  PubMed  CAS  Google Scholar 

  20. Hofmann MA, Lalla E, Lu Y et al (2001) Hyperhomocysteinemia enhances vascular inflammation and accelerates atherosclerosis in a murine model. J Clin Invest 107(6):675–683

    Article  PubMed  CAS  Google Scholar 

  21. Dayal S, Wilson KM, Leo L et al (2006) Enhanced susceptibility to arterial thrombosis in a murine model of hyperhomocysteinemia. Blood 108(7):2237–2243

    Article  PubMed  CAS  Google Scholar 

  22. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodeling. Nat Rev Mol Cell Biol 8(3):221–233

    Article  PubMed  CAS  Google Scholar 

  23. Moshal KS, Metreveli N, Frank I, Tyagi SC (2008) Mitochondrial MMP activation, dysfunction and arrythmogenesis in hyperhomocyteienemia. Curr Vasc Pharmacol 6(2):84–92

    Article  PubMed  CAS  Google Scholar 

  24. Raffetto JD, Khalil RA (2008) Matrix metalloproteinases and their inhibitors in vascular remodeling and vascular disease. Curr Vasc Pharmacol 6(3):158–172

    Article  PubMed  CAS  Google Scholar 

  25. Chase AJ, Newby AC (2003) Regulation of matrix metalloproteinase (matrixin) genes in blood vessels: a multi-step recruitment model for pathological remodelling. J Vasc Res 40(4):329–343

    Article  PubMed  CAS  Google Scholar 

  26. Weiss N, Heydrick S, Zhang YY, Bierl C, Cap A, Loscalzo J (2002) Cellular redox state and endothelial dysfunction in mildly hyperhomocysteinemic cystathionine β-synthase-deficient mice. Arterioscler Thromb Vasc Biol 22:34–41

    Article  PubMed  CAS  Google Scholar 

  27. Sen U, Basu P, Abe OA et al. (2009) Hydrogen sulfide ameliorates hyperhomocysteinemia associated chronic renal failure. Am J Physiol Renal Physiol doi:10.1152/ajprenal.00145.2009

  28. Jiang X, Yang F, Tan H, Liao D, Bryan RM Jr, Randhawa JK, Rumbaut RE, Durante W, Schafer AI, Yang X, Wang H (2005) Hyperhomocystinemia impairs endothelial function and eNOS activity via PKC activation. Arterioscler Thromb Vasc Biol 25(12):2515–2521 Dec

    Article  PubMed  CAS  Google Scholar 

  29. Tyagi SC, Lominadze D, Roberts AM (2005) Homocysteine in microvascular endothelial barrier permeability. Cell Biochem Biophys 43(1):37–44

    Article  PubMed  CAS  Google Scholar 

  30. Lominadze D, Roberts AM, Tyagi N et al (2006) Homocysteine causes cerebrovascular leakage in mice. Am J Physiol Heart Circ Physiol 290(3):H1206–H1213

    Article  PubMed  CAS  Google Scholar 

  31. Gratton MA, Rao VH, Meehan DT et al (2005) Matrix metalloproteinase dysregulation in the stria vascularis of mice with Alport syndrome: implications for capillary basement membrane pathology. Am J Pathol 166:1465–1474

    PubMed  CAS  Google Scholar 

  32. Zhang X, Li H, Jin H et al (2000) Effects of homocysteine on endothelial nitric oxide production. Am J Physiol Renal Physiol 279:F671–F678

    PubMed  CAS  Google Scholar 

  33. Tyagi N, Sedoris KC, Steed M et al (2005) Mechanisms of Homocysteine induced oxidative stress. Am J Physiol Heart Circ Physiol 289(6):H2649–H2656

    Article  PubMed  CAS  Google Scholar 

  34. Postea O, Krotz F, Henger A et al (2006) Stereospecific and redox-sensitive increase in monocyte adhesion to endothelial cells by homocysteine. Arterioscler Thromb Vasc Biol 26:508–513

    Article  PubMed  CAS  Google Scholar 

  35. Shi X, Han W, Yamamoto H et al (2007) Nitric oxide and mitochondrial status in noise-induced hearing loss. Free Radic Res 41(2):1313–1325

    Article  PubMed  CAS  Google Scholar 

  36. Heydrick SJ, Weiss N, Thomas SR et al (2004) l-Homocysteine and l-homocystine stereospecifically induce endothelial nitric oxide synthase-dependent lipid peroxidation in endothelial cells. Free Radic Biol Med 36:632–640

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

A part of this study was supported by NIH grants- HL-71010; HL-74185; HL-88012; and NS-51568.

Author information

Authors and Affiliations

  1. Department of Physiology & Biophysics, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY, 40202, USA

    Soumi Kundu, Neetu Tyagi, Utpal Sen & Suresh C. Tyagi

Authors
  1. Soumi Kundu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Neetu Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Utpal Sen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Suresh C. Tyagi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Suresh C. Tyagi.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kundu, S., Tyagi, N., Sen, U. et al. Matrix imbalance by inducing expression of metalloproteinase and oxidative stress in cochlea of hyperhomocysteinemic mice. Mol Cell Biochem 332, 215–224 (2009). https://doi.org/10.1007/s11010-009-0194-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-009-0194-2

Keywords

Search

Navigation