PMID- 22222235
OWN - NLM
STAT- MEDLINE
DCOM- 20120710
LR  - 20211021
IS  - 1878-5891 (Electronic)
IS  - 0378-5955 (Print)
IS  - 0378-5955 (Linking)
VI  - 284
IP  - 1-2
DP  - 2012 Feb
TI  - Folic acid improves inner ear vascularization in hyperhomocysteinemic mice.
PG  - 42-51
LID - 10.1016/j.heares.2011.12.006 [doi]
AB  - 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 mug/g/day, equivalent to a 400 mug/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.
CI  - Copyright (c) 2011 Elsevier B.V. All rights reserved.
FAU - Kundu, Soumi
AU  - Kundu S
AD  - Department of Genetics and Pathology, Uppsala University, Dag Hammarskjolds vag 
      20, Rudbecklaboratoriet C11 PLAN 3, 751 85 Uppsala, Sweden.
FAU - Munjal, Charu
AU  - Munjal C
FAU - Tyagi, Neetu
AU  - Tyagi N
FAU - Sen, Utpal
AU  - Sen U
FAU - Tyagi, Aaron C
AU  - Tyagi AC
FAU - Tyagi, Suresh C
AU  - Tyagi SC
LA  - eng
GR  - R01 HL071010/HL/NHLBI NIH HHS/United States
GR  - R01 NS051568/NS/NINDS NIH HHS/United States
GR  - HL-71010/HL/NHLBI NIH HHS/United States
GR  - NS-51568/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111224
PL  - Netherlands
TA  - Hear Res
JT  - Hearing research
JID - 7900445
RN  - 0 (Collagen Type IV)
RN  - 0 (RNA, Messenger)
RN  - 935E97BOY8 (Folic Acid)
RN  - EC 1.5.1.20 (Methylenetetrahydrofolate Reductase (NADPH2))
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
RN  - EC 4.2.1.22 (Cystathionine beta-Synthase)
SB  - IM
CIN - Hear Res. 2012 Dec;294(1-2):166-7; author reply 168-70. PMID: 22634391
MH  - Adult
MH  - Animals
MH  - Auditory Threshold/drug effects/physiology
MH  - Cochlea/blood supply/drug effects/physiopathology
MH  - Collagen Type IV/genetics/metabolism
MH  - Cystathionine beta-Synthase/genetics/metabolism
MH  - Ear, Inner/*blood supply/*drug effects/physiopathology
MH  - Evoked Potentials, Auditory, Brain Stem/drug effects
MH  - Folic Acid/*pharmacology
MH  - Hearing Loss/etiology/genetics/physiopathology
MH  - Heterozygote
MH  - Humans
MH  - Hyperhomocysteinemia/complications/*drug therapy/genetics/*physiopathology
MH  - Male
MH  - Matrix Metalloproteinase 9/genetics/metabolism
MH  - Metabolic Networks and Pathways
MH  - Methylenetetrahydrofolate Reductase (NADPH2)/genetics/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Oxidative Stress/drug effects
MH  - RNA, Messenger/genetics/metabolism
PMC - PMC3609427
MID - NIHMS346956
EDAT- 2012/01/10 06:00
MHDA- 2012/07/11 06:00
PMCR- 2013/03/27
CRDT- 2012/01/07 06:00
PHST- 2011/08/03 00:00 [received]
PHST- 2011/11/22 00:00 [revised]
PHST- 2011/12/09 00:00 [accepted]
PHST- 2012/01/07 06:00 [entrez]
PHST- 2012/01/10 06:00 [pubmed]
PHST- 2012/07/11 06:00 [medline]
PHST- 2013/03/27 00:00 [pmc-release]
AID - S0378-5955(11)00299-1 [pii]
AID - 10.1016/j.heares.2011.12.006 [doi]
PST - ppublish
SO  - Hear Res. 2012 Feb;284(1-2):42-51. doi: 10.1016/j.heares.2011.12.006. Epub 2011 
      Dec 24.