PMID- 21383673
OWN - NLM
STAT- MEDLINE
DCOM- 20110629
LR  - 20230216
IS  - 1530-0307 (Electronic)
IS  - 0023-6837 (Print)
IS  - 0023-6837 (Linking)
VI  - 91
IP  - 5
DP  - 2011 May
TI  - Arterial pathology in canine mucopolysaccharidosis-I and response to therapy.
PG  - 665-74
LID - 10.1038/labinvest.2011.7 [doi]
AB  - Mucopolysaccharidosis-I (MPS-I) is an inherited deficiency of alpha-L-iduronidase 
      (IdU) that causes lysosomal accumulation of glycosaminoglycans (GAG) in a variety 
      of parenchymal cell types and connective tissues. The fundamental link between 
      genetic mutation and tissue GAG accumulation is clear, but relatively little 
      attention has been given to the morphology or pathogenesis of associated lesions, 
      particularly those affecting the vascular system. The terminal parietal branches 
      of the abdominal aorta were examined from a colony of dogs homozygous (MPS-I 
      affected) or heterozygous (unaffected carrier) for an IdU mutation that 
      eliminated all enzyme activity, and in affected animals treated with human 
      recombinant IdU. High-resolution computed tomography showed that vascular wall 
      thickenings occurred in affected animals near branch points, and associated with 
      low endothelial shear stress. Histologically these asymmetric 'plaques' entailed 
      extensive intimal thickening with disruption of the internal elastic lamina, 
      occluding more than 50% of the vascular lumen in some cases. Immunohistochemistry 
      was used to show that areas of sclerosis contained foamy (GAG laden) macrophages, 
      fibroblasts and smooth muscle cells, with loss of overlying endothelial basement 
      membrane and claudin-5 expression. Lesions contained scattered cells expressing 
      nuclear factor-kappabeta (p65), increased fibronectin and transforming growth factor beta-1 
      signaling (with nuclear Smad3 accumulation) in comparison to unaffected vessels. 
      Intimal lesion development and morphology was improved by intravenous recombinant 
      enzyme treatment, particularly with immune tolerance to this exogenous protein. 
      The progressive sclerotic vasculopathy of MPS-I shares some morphological and 
      molecular similarities to atherosclerosis, including formation in areas of low 
      shear stress near branch points, and can be reduced or inhibited by intravenous 
      administration of recombinant IdU.
FAU - Lyons, Jeremiah A
AU  - Lyons JA
AD  - Department of Pathobiology, University of Tennessee, Knoxville, TN, USA.
FAU - Dickson, Patricia I
AU  - Dickson PI
FAU - Wall, Jonathan S
AU  - Wall JS
FAU - Passage, Merry B
AU  - Passage MB
FAU - Ellinwood, N Matthew
AU  - Ellinwood NM
FAU - Kakkis, Emil D
AU  - Kakkis ED
FAU - McEntee, Michael F
AU  - McEntee MF
LA  - eng
GR  - R56 DK066448/DK/NIDDK NIH HHS/United States
GR  - P40 RR002512/RR/NCRR NIH HHS/United States
GR  - R01 DK066448/DK/NIDDK NIH HHS/United States
GR  - R01 NS054242/NS/NINDS NIH HHS/United States
GR  - RR002512/RR/NCRR NIH HHS/United States
GR  - DK066448/DK/NIDDK NIH HHS/United States
GR  - NS054242/NS/NINDS NIH HHS/United States
GR  - R01 NS054242-05/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20110307
PL  - United States
TA  - Lab Invest
JT  - Laboratory investigation; a journal of technical methods and pathology
JID - 0376617
RN  - 0 (Recombinant Proteins)
RN  - EC 3.2.1.76 (Iduronidase)
SB  - IM
MH  - Animals
MH  - Arteries/*pathology
MH  - Dogs
MH  - Female
MH  - Humans
MH  - Iduronidase/administration & dosage/genetics/therapeutic use
MH  - Immunohistochemistry
MH  - Male
MH  - Mucopolysaccharidosis I/genetics/pathology/therapy/*veterinary
MH  - Recombinant Proteins/administration & dosage/genetics/therapeutic use
MH  - Tomography, X-Ray Computed
MH  - Vascular Diseases/genetics/pathology/therapy/*veterinary
PMC - PMC3084338
MID - NIHMS255513
COIS- Conflict of interest: none declared.
EDAT- 2011/03/09 06:00
MHDA- 2011/06/30 06:00
PMCR- 2011/11/01
CRDT- 2011/03/09 06:00
PHST- 2011/03/09 06:00 [entrez]
PHST- 2011/03/09 06:00 [pubmed]
PHST- 2011/06/30 06:00 [medline]
PHST- 2011/11/01 00:00 [pmc-release]
AID - S0023-6837(22)02781-7 [pii]
AID - 10.1038/labinvest.2011.7 [doi]
PST - ppublish
SO  - Lab Invest. 2011 May;91(5):665-74. doi: 10.1038/labinvest.2011.7. Epub 2011 Mar 
      7.