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Thromb Res ; 169: 105-112, 2018 09.
Article in English | MEDLINE | ID: mdl-30031289

ABSTRACT

BACKGROUND: Hypoxia within acute venous thrombi is thought to drive resolution through stabilisation of hypoxia inducible factor 1 alpha (HIF1α). Prolyl hydroxylase domain (PHD) isoforms are critical regulators of HIF1α stability. Non-selective inhibition of PHD isoforms with l-mimosine has been shown to increase HIF1α stabilisation and promote thrombus resolution. OBJECTIVE: The aim of this study was to investigate the therapeutic potential of PHD inhibition in venous thrombus resolution. METHODS: Thrombosis was induced in the inferior vena cava of mice using a combination of flow restriction and endothelial activation. Gene and protein expression of PHD isoforms in the resolving thrombus was measured by RT-PCR and immunohistochemistry. Thrombus resolution was quantified in mice treated with pan PHD inhibitors AKB-4924 and JNJ-42041935 or inducible all-cell Phd2 knockouts by micro-computed tomography, 3D high frequency ultrasound or endpoint histology. RESULTS: Resolving venous thrombi demonstrated significant temporal gene expression profiles for PHD2 and PHD3 (P < 0.05), but not for PHD1. PHD isoform protein expression was localised to early and late inflammatory cell infiltrates. Treatment with selective pan PHD inhibitors, AKB-4924 and JNJ-42041935, enhanced thrombus neovascularisation (P < 0.05), but had no significant effect on overall thrombus resolution. Thrombus resolution or its markers, macrophage accumulation and neovascularisation, did not differ significantly in inducible all-cell homozygous Phd2 knockouts compared with littermate controls (P > 0.05). CONCLUSIONS: This data suggests that PHD-mediated thrombus neovascularisation has a limited role in the resolution of venous thrombi. Directly targeting angiogenesis alone may not be a viable therapeutic strategy to enhance venous thrombus resolution.


Subject(s)
Benzimidazoles/therapeutic use , Hypoxia-Inducible Factor-Proline Dioxygenases/antagonists & inhibitors , Neovascularization, Physiologic/drug effects , Piperazines/therapeutic use , Procollagen-Proline Dioxygenase/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyridones/therapeutic use , Thrombosis/drug therapy , Animals , Female , Humans , Hypoxia-Inducible Factor-Proline Dioxygenases/genetics , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Procollagen-Proline Dioxygenase/genetics , Thrombosis/genetics , Thrombosis/pathology , Transcriptome
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