Upregulation of PAI-1 is mediated through TGF-β/Smad pathway in transplant arteriopathy

Chunming Dong, Shoukang Zhu, Tao Wang, Woohyun Yoon, Pascal J. Goldschmidt-Clermont

Research output: Contribution to journalArticle

28 Scopus citations

Abstract

Background: Plasminogen activator inhibitor type 1 (PAI-1) is the primary physiologic inhibitor of plasminogen activator in vivo. Increased PAI-1 expression is associated with arteriosclerosis. Transforming growth factor-beta (TGF-β) induces PAI-1 production via Smads. Methods: In vivo, TGF-β receptors (TβRs), Smad2, Smad3, and Smad4, PAI-1, and Smad2 phosphorylation were examined by immunohistochemistry in 3 native aortas, 14 rat aortic syngrafts, and 19 allografts collected at 15, 30, and 45 days post-transplantation. In vitro, phosphorylation of Smad2 and induction of PAI-1 mRNA in human aortic smooth muscle cells (SMCs) in response to TGF-β treatment were detected by Western blot and by TaqMan real-time RT-PCR, respectively. Results: Immunohistochemical staining revealed that vascular parenchymal cells contained TβRI, TβRII, Smad2, Smad3, and Smad4, known signaling transducers for TGF-β/Smad pathway, in all samples. Intense staining for phospho-Smad2 was observed in 94% of endothelial cells (ECs), 86% of intimal cells, 27% of medial SMCs, and 38% of adventitial cells at all 3 time points in all aortic allografts, but only in 5% of ECs in syngrafts. PAI-1 immunoreactivity was detected in similar number of cells, and from consecutive sections, phospho-Smad2 colocalized with PAI-1, in the aortic allografts. Low basal level PAI-1 expression was observed in aortic syngrafts and native vessels. Smad2 phosphorylation and time-dependent PAI-1 induction were detected in cultured SMCs upon TGF-β treatment. Conclusions: Phospho-Smad2 staining in aortic allografts indicates the activation of TGF-β signaling in allo-transplantation; and co-localization of PAI-1 and phospho-Smad2 suggests that PAI-1 upregulation is mediated mainly by TGF-β/Smad pathway in aortic allografts.

Original languageEnglish (US)
Pages (from-to)999-1008
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume21
Issue number9
DOIs
StatePublished - Sep 1 2002

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

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