RGD Reference Report - Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis. - Rat Genome Database

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Impaired fibrinolytic system in ApoE gene-deleted mice with hyperlipidemia augments deep vein thrombosis.

Authors: Diaz, JA  Ballard-Lipka, NE  Farris, DM  Hawley, AE  Wrobleski, SK  Myers, DD  Henke, PK  Lawrence, DA  Wakefield, TW 
Citation: Diaz JA, etal., J Vasc Surg. 2012 Mar;55(3):815-22. Epub 2011 Nov 25.
RGD ID: 6903200
Pubmed: PMID:22119245   (View Abstract at PubMed)
PMCID: PMC3289767   (View Article at PubMed Central)
DOI: DOI:10.1016/j.jvs.2011.08.038   (Journal Full-text)

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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
familial hyperlipidemia  ISOPlau (Mus musculus)6903200; 6903200associated with Venous Thrombosis more ...RGD 
familial hyperlipidemia  IEP 6903200associated with Venous Thrombosis more ...RGD 
Venous Thrombosis  ISOApoe (Mus musculus)6903200; 6903200 RGD 
Venous Thrombosis  IMP 6903200 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Apoe  (apolipoprotein E)
Plau  (plasminogen activator, urokinase)

Genes (Mus musculus)
Apoe  (apolipoprotein E)
Plau  (plasminogen activator, urokinase)

Genes (Homo sapiens)
APOE  (apolipoprotein E)
PLAU  (plasminogen activator, urokinase)


Additional Information