Document Detail


Multifaceted role of plasminogen activator inhibitor-1 in regulating early remodeling of vein bypass grafts.
MedLine Citation:
PMID:  21571686     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
OBJECTIVE: The role of plasminogen activator inhibitor-1 (PAI-1) in vein graft (VG) remodeling is undefined. We examined the effect of PAI-1 on VG intimal hyperplasia and tested the hypothesis that PAI-1 regulates VG thrombin activity.
METHODS AND RESULTS: VGs from wild-type (WT), Pai1(-/-), and PAI-1-transgenic mice were implanted into WT, Pai1(-/-), or PAI-1-transgenic arteries. VG remodeling was assessed 4 weeks later. Intimal hyperplasia was significantly greater in PAI-1-deficient mice than in WT mice. The proliferative effect of PAI-1 deficiency was retained in vitronectin-deficient mice, suggesting that PAI-1's antiproteolytic function plays a key role in regulating intimal hyperplasia. Thrombin-induced proliferation of PAI-1-deficient venous smooth muscle cells (SMC) was significantly greater than that of WT SMC, and thrombin activity was significantly higher in PAI-1-deficient VGs than in WT VGs. Increased PAI-1 expression, which has been associated with obstructive VG disease, did not increase intimal hyperplasia.
CONCLUSIONS: Decreased PAI-1 expression (1) promotes intimal hyperplasia by pathways that do not require vitronectin and (2) increases thrombin activity in VG. PAI-1 overexpression, although it promotes SMC migration in vitro, did not increase intimal hyperplasia. These results challenge the concept that PAI-1 drives nonthrombotic obstructive disease in VG and suggest that PAI-1's antiproteolytic function, including its antithrombin activity, inhibits intimal hyperplasia.
Authors:
Yan Ji; Tammy L Strawn; Elizabeth A Grunz; Meredith J Stevenson; Alexander W Lohman; Daniel A Lawrence; William P Fay
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2011-05-12
Journal Detail:
Title:  Arteriosclerosis, thrombosis, and vascular biology     Volume:  31     ISSN:  1524-4636     ISO Abbreviation:  Arterioscler. Thromb. Vasc. Biol.     Publication Date:  2011 Aug 
Date Detail:
Created Date:  2011-07-21     Completed Date:  2011-09-20     Revised Date:  2014-09-19    
Medline Journal Info:
Nlm Unique ID:  9505803     Medline TA:  Arterioscler Thromb Vasc Biol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1781-7     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Movement
Cell Proliferation
Coronary Artery Bypass / adverse effects
Fibrin / metabolism
Fibrinogen / metabolism
Gene Expression
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myocytes, Smooth Muscle / pathology,  physiology
Neointima / etiology,  pathology,  physiopathology
Serpin E2 / deficiency,  genetics,  physiology*
Tunica Intima / pathology
Vena Cava, Inferior / pathology,  transplantation*
Vitronectin / deficiency
Grant Support
ID/Acronym/Agency:
HL54710/HL/NHLBI NIH HHS; HL55374/HL/NHLBI NIH HHS; HL57346/HL/NHLBI NIH HHS; HL89407/HL/NHLBI NIH HHS; HL95951/HL/NHLBI NIH HHS; R01 HL095951/HL/NHLBI NIH HHS; R01 HL095951-01A2/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Serpin E2; 0/Serpine2 protein, mouse; 0/Vitronectin; 9001-31-4/Fibrin; 9001-32-5/Fibrinogen
Comments/Corrections

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