Matrix imbalance by inducing expression of metalloproteinase and oxidative stress in cochlea of hyperhomocysteinemic mice.
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 beta-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 p22(phox) in cochlea. It is thus suggested that Hcy induced matrix imbalance, structural changes and oxidative stress in cochlea.
Kundu
Soumi
S
Department of Physiology & Biophysics, University of Louisville School of Medicine, 500 South Preston Street, Louisville, KY 40202, USA.
Tyagi
Neetu
N
Sen
Utpal
U
Tyagi
Suresh C
SC
D000818:Animals; D015153:Blotting, Western; D003051:Cochlea / Q000201:enzymology* / Q000473:pathology*; D003541:Cystathionine beta-Synthase / Q000502:physiology; D005109:Extracellular Matrix / Q000201:enzymology* / Q000473:pathology; D006710:Homocysteine / Q000378:metabolism; D020138:Hyperhomocysteinemia / Q000201:enzymology* / Q000473:pathology*; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism
D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D006710:Homocysteine; D020782:Matrix Metalloproteinases; D003541:Cystathionine beta-Synthase