The perlecan fragment LG3 is a novel regulator of obliterative remodeling associated with allograft vascular rejection

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DOIResolve DOI: http://doi.org/10.1161/CIRCRESAHA.111.250431
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TypeArticle
Journal titleCirculation Research
ISSN0009-7330
Volume110
Issue1
Pages94104; # of pages: 11
Subjectapoptosis; endothelial cell; extracellular matrix; neointima; kidney
AbstractRATIONALE: Endothelial apoptosis is increased in association with acute and chronic vascular rejection (VR) of solid allografts. Apoptotic endothelial cells (EC) release LG3, a C-terminal fragment of perlecan of potential importance in vascular remodeling and neointima formation. OBJECTIVE: Our 2 goals were to determine whether circulating levels of LG3 are increased in association with acute VR of renal allografts and to evaluate the impact of LG3 on vascular remodeling. METHODS AND RESULTS: We conducted a case-control study to compare serum LG3 levels in human renal transplant patients with acute VR, tubulo-interstitial rejection (ATIR) and normal graft function. Aorta transplantation between fully MHC-mismatched mice in association with intravenous LG3 injection was used to characterize the impact of LG3 on vascular remodeling. Scratch assays evaluated the promigratory activity of LG3 on vascular smooth muscle cells (VSMC) in vitro. Serum LG3 levels were significantly elevated in human renal transplant patients with acute VR (n = 16) compared to ATIR (n = 16) and normal graft function (n = 32, P = 0.004). In patients with acute VR, graft loss was associated with elevated LG3 levels. Increasing LG3 serum levels in aortic allograft recipients significantly increased neointima formation. LG3 injection fostered accumulation of α-smooth muscle actin-positive cells and decreased the number of CD31 positive EC. LG3 increased the migration of VSMC through extracellular signal-regulated kinases 1/2-dependent pathways. CONCLUSION: These results indicate that LG3 is a novel regulator of obliterative vascular remodeling during rejection.
Publication date
PublisherAmerican Heart Association
LanguageEnglish
AffiliationNRC Biotechnology Research Institute; National Research Council Canada
Peer reviewedYes
NRC number53205
NPARC number21268298
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Record identifier7c59ea9e-54e6-40f0-b624-38935a1ddc50
Record created2013-06-17
Record modified2016-05-09
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