PMID- 22119245
OWN - NLM
STAT- MEDLINE
DCOM- 20120501
LR  - 20220318
IS  - 1097-6809 (Electronic)
IS  - 0741-5214 (Print)
IS  - 0741-5214 (Linking)
VI  - 55
IP  - 3
DP  - 2012 Mar
TI  - Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia 
      augments deep vein thrombosis.
PG  - 815-22
LID - 10.1016/j.jvs.2011.08.038 [doi]
AB  - BACKGROUND: Hyperlipidemia increases the level of blood plasminogen activator 
      inhibitor-1 (PAI-1) that is responsible for regulating fibrinolysis by inhibiting 
      both urokinase-type plasminogen activator (u-PA) and tissue-type plasminogen 
      activator (t-PA). While this fibrinolytic pathway is well known, the role of 
      PAI-1 in venous thrombosis (VT) under hyperlipidemic conditions has not been 
      fully established. We sought to determine the effects of PAI-1 in an in vivo 
      hyperlipidemic model of VT. METHODS: C57BL/6 wild-type (WT) mice, apolipoprotein 
      E gene-deleted mice (ApoE-/-) having hyperlipidemia, and PAI-1 gene-deleted 
      (PAI-1-/-) mice were used in this study. Inferior vena cava (IVC) ligation below 
      the level of the renal veins was performed to create a stasis VT. Endpoints 
      included measuring acute thrombosis (day 2) and chronic thrombosis (days 6 and 
      14). At euthanasia, blood samples were collected for plasmin and PAI-1 activity. 
      In addition, the IVC and its thrombus were evaluated for thrombus weight (TW), 
      u-PA activity, and differential leukocyte count while the vein wall only was 
      analyzed for monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinase 
      (MMP) 2, and MMP-9. RESULTS: Compared to WT at day 2, ApoE-/-mice demonstrated a 
      statistically significant 14% increase in TW (P < .05) and a significant 41% 
      increase in circulating PAI-1 activity (P < .05), while showing a trend of 
      decreased plasmin activity. In addition, TW in ApoE-/-mice was 45% higher than 
      PAI-1-/-mice at day 2 (P < .05), 33% at day 6 (P < .01), and 41% at day 14 (P < 
      .01). ApoE-/-mice exhibited undetectable levels of u-PA in both vein wall and 
      thrombus, compared to WT, at all time points. Also, vein wall MMP-2 was 
      significantly decreased by 64% at day 6 (P < .01) and 58% at day 14 (P < .05). 
      MMP-9 was significantly decreased by 71% at day 2 (P < .01) and 48% at day 6 (P < 
      .01), in ApoE-/-mice compared to WT mice. In addition, in ApoE-/-mice, MCP-1 was 
      significantly decreased by 38% at day 2 (P < .01) and 67% at day 6 (P < .01) vs 
      WT mice. As expected in ApoE mice, following a decrease in MCP-1, monocyte 
      recruitment was significantly decreased at days 6 (P < .01) and 14 (P < .05). 
      CONCLUSIONS: A significant increase of circulating PAI-1 levels in hyperlipidemic 
      mice correlated with an early increase in TW due to impaired fibrinolysis. The 
      undetectable levels of u-PA in ApoE-/-mice correlated to a decrease in vein wall 
      MMP-2, MMP-9, MCP-1, and a decrease in monocyte recruitment diminishing thrombus 
      resolution.
CI  - Copyright (c) 2012 Society for Vascular Surgery. Published by Mosby, Inc. All 
      rights reserved.
FAU - Diaz, Jose A
AU  - Diaz JA
AD  - Department of Surgery, Section of Vascular Surgery, Conrad Jobst Vascular 
      Research Laboratories, University of Michigan, Ann Arbor, MI 48109, USA. 
      josediaz@med.umich.edu
FAU - Ballard-Lipka, Nicole E
AU  - Ballard-Lipka NE
FAU - Farris, Diana M
AU  - Farris DM
FAU - Hawley, Angela E
AU  - Hawley AE
FAU - Wrobleski, Shirley K
AU  - Wrobleski SK
FAU - Myers, Daniel D
AU  - Myers DD
FAU - Henke, Peter K
AU  - Henke PK
FAU - Lawrence, Daniel A
AU  - Lawrence DA
FAU - Wakefield, Thomas W
AU  - Wakefield TW
LA  - eng
GR  - P01 HL089407/HL/NHLBI NIH HHS/United States
GR  - P01 HL089407-01A1/HL/NHLBI NIH HHS/United States
GR  - 1P01HL089407/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20111125
PL  - United States
TA  - J Vasc Surg
JT  - Journal of vascular surgery
JID - 8407742
RN  - 0 (Apolipoproteins E)
RN  - 0 (Ccl2 protein, mouse)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Plasminogen Activator Inhibitor 1)
RN  - EC 3.4.21.7 (Fibrinolysin)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
RN  - EC 3.4.24.24 (Matrix Metalloproteinase 2)
RN  - EC 3.4.24.24 (Mmp2 protein, mouse)
RN  - EC 3.4.24.35 (Matrix Metalloproteinase 9)
RN  - EC 3.4.24.35 (Mmp9 protein, mouse)
SB  - IM
MH  - Animals
MH  - Apolipoproteins E/*deficiency/genetics
MH  - Chemokine CCL2/metabolism
MH  - Disease Models, Animal
MH  - Fibrinolysin/metabolism
MH  - *Fibrinolysis/genetics
MH  - Hyperlipidemias/blood/*complications/genetics
MH  - Leukocyte Count
MH  - Ligation
MH  - Male
MH  - Matrix Metalloproteinase 2/metabolism
MH  - Matrix Metalloproteinase 9/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Plasminogen Activator Inhibitor 1/deficiency/genetics
MH  - Time Factors
MH  - Urokinase-Type Plasminogen Activator/metabolism
MH  - Vena Cava, Inferior/*metabolism/surgery
MH  - Venous Thrombosis/blood/*etiology
PMC - PMC3289767
MID - NIHMS321465
EDAT- 2011/11/29 06:00
MHDA- 2012/05/02 06:00
PMCR- 2013/03/01
CRDT- 2011/11/29 06:00
PHST- 2011/05/27 00:00 [received]
PHST- 2011/08/18 00:00 [revised]
PHST- 2011/08/21 00:00 [accepted]
PHST- 2011/11/29 06:00 [entrez]
PHST- 2011/11/29 06:00 [pubmed]
PHST- 2012/05/02 06:00 [medline]
PHST- 2013/03/01 00:00 [pmc-release]
AID - S0741-5214(11)01969-0 [pii]
AID - 10.1016/j.jvs.2011.08.038 [doi]
PST - ppublish
SO  - J Vasc Surg. 2012 Mar;55(3):815-22. doi: 10.1016/j.jvs.2011.08.038. Epub 2011 Nov 
      25.