Folic acid improves inner ear vascularization in hyperhomocysteinemic mice.
More than 29 million adults in the United States have been diagnosed with hearing loss. Interestingly, elevated homocysteine (Hcy) levels, known as hyperhomocysteinemia (HHcy), are also associated with impaired hearing. However, the associated mechanism remains obscure. The collagen receptor such as discoidin domain receptor 1 and matrix metalloproteinase (MMP) play a significant role in inner ear structure and function. We hypothesize that HHcy increases hearing thresholds by compromise in inner ear vasculature resulted from impaired Hcy metabolism, increased oxidative stress, collagen IVa and collagen Ia turnover. The treatment with folic acid (FA) protects elevated hearing thresholds and prevents reduction in vessel density by lowering abundant collagen deposition and oxidative stress in inner ear. To test this hypothesis we employed 8 weeks old male wild type (WT), cystathionine-beta-synthase heterozygote knockout (CBS+/-) mice, WT + FA (0.0057 μg/g/day, equivalent to a 400 μg/70 kg/day human dose in drinking water); and CBS(+/-) +FA. The mice were treated for four weeks. The hearing thresholds were determined by recording the auditory brainstem responses. Integrity of vessels was analyzed by perfusion of horseradish peroxidase (HRP) tracer. Endothelial permeability was assessed, which indicated restoration of HRP leakage by FA treatment. A total Hcy level was increased in stria vascularis (SV) and spiral ligament (SL) of CBS+/- mice which was lowered by FA. Interestingly, FA treatment lowered Col IVa Immunostaining by affecting its turnover. The levels of MMP-2, -9, methylenetetrahydrofolate reductase (MTHFR) and cystathione gamma lyase (CSE) were measured by Western blot analysis. The oxidative stress was high in SV and SL of CBS+/- compared to WT however the treatment with FA lowered oxidative stress in CBS+/- mice. These data suggested that hearing loss in CBS+/- mice was primarily due to leakage in inner ear circulation, also partly by induced collagen imbalance, increase in Hcy and oxidative stress in inner ear.
Department of Genetics and Pathology, Uppsala University, Dag Hammarskjölds väg 20, Rudbecklaboratoriet C11 PLAN 3, 751 85 Uppsala, Sweden.
Soumi
S
Kundu
Charu
C
Munjal
Neetu
N
Tyagi
Utpal
U
Sen
Aaron C
AC
Tyagi
Suresh C
SC
Tyagi
D000328:Adult; D000818:Animals; D001309:Auditory Threshold / Q000187:drug effects / Q000502:physiology; D003051:Cochlea / Q000098:blood supply / Q000187:drug effects / Q000503:physiopathology; D024141:Collagen Type IV / Q000235:genetics / Q000378:metabolism; D003541:Cystathionine beta-Synthase / Q000235:genetics / Q000378:metabolism; D007758:Ear, Inner / Q000098:blood supply* / Q000187:drug effects* / Q000503:physiopathology; D016057:Evoked Potentials, Auditory, Brain Stem / Q000187:drug effects; D005492:Folic Acid / Q000494:pharmacology*; D034381:Hearing Loss / Q000209:etiology / Q000235:genetics / Q000503:physiopathology; D006579:Heterozygote; D006801:Humans; D020138:Hyperhomocysteinemia / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D024141:Collagen Type IV; D012333:RNA, Messenger; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; D003541:Cystathionine beta-Synthase