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Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen.

ABSTRACT: Thrombosis and cardiovascular disease (CVD) represent major causes of morbidity and mortality. Low androgen correlates with higher incidence of CVD/thrombosis. Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VIIa (TF-FVIIa)-dependent FXa generation. Because endothelial cell (EC) dysfunction leading to vascular disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the natural expression of TFPI. Data mining of NCBI's GEO microarrays revealed strong coexpression between TFPI and the uncharacterized protein encoded by C6ORF105, which is predicted to be multispan, palmitoylated and androgen-responsive. We demonstrate that this protein regulates both the native and androgen-enhanced TFPI expression and activity in cultured ECs, and we named it androgen-dependent TFPI-regulating protein (ADTRP). We confirm ADTRP expression and colocalization with TFPI and caveolin-1 in ECs. ADTRP-shRNA reduces, while over-expression of ADTRP enhances, TFPI mRNA and activity and the colocalization of TF-FVIIa-FXa-TFPI with caveolin-1. Imaging and Triton X-114-extraction confirm TFPI and ADTRP association with lipid rafts/caveolae. Dihydrotestosterone up-regulates TFPI and ADTRP expression, and increases FXa inhibition by TFPI in an ADTRP- and caveolin-1-dependent manner. We conclude that the ADTRP-dependent up-regulation of TFPI expression and activity by androgen represents a novel mechanism of increasing the anticoagulant protection of the endothelium.

SUBMITTER: Lupu C

PROVIDER: S-EPMC3204913 | biostudies-literature | 2011 Oct

REPOSITORIES: biostudies-literature

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Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen.

Lupu Cristina C Zhu Hua H Popescu Narcis I NI Wren Jonathan D JD Lupu Florea F

Blood 20110825 16

Thrombosis and cardiovascular disease (CVD) represent major causes of morbidity and mortality. Low androgen correlates with higher incidence of CVD/thrombosis. Tissue Factor Pathway Inhibitor (TFPI) is the major inhibitor of tissue factor-factor VIIa (TF-FVIIa)-dependent FXa generation. Because endothelial cell (EC) dysfunction leading to vascular disease correlates with low EC-associated TFPI, we sought to identify mechanisms that regulate the natural expression of TFPI. Data mining of NCBI's G ...[more]

PMID: 21868574

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Project description:Background The physiological function of ADTRP (androgen-dependent tissue factor pathway inhibitor regulating protein) is unknown. We previously identified ADTRP as coregulating with and supporting the anticoagulant activity of tissue factor pathway inhibitor in endothelial cells in vitro. Here, we studied the role of ADTRP in vivo, specifically related to vascular development, stability, and function. Methods and Results Genetic inhibition of Adtrp produced vascular malformations in the low-pressure vasculature of zebrafish embryos and newborn mice: dilation/tortuosity, perivascular inflammation, extravascular proteolysis, increased permeability, and microhemorrhages, which produced partially penetrant lethality. Vascular leakiness correlated with decreased endothelial cell junction components VE -cadherin and claudin-5. Changes in hemostasis in young adults comprised modest decrease of tissue factor pathway inhibitor antigen and activity and increased tail bleeding time and volume. Cell-based reporter assays revealed that ADTRP negatively regulates canonical Wnt signaling, affecting membrane events downstream of low-density lipoprotein receptor-related protein 6 ( LRP 6) and upstream of glycogen synthase kinase 3 beta. ADTRP deficiency increased aberrant/ectopic Wnt/?-catenin signaling in vivo in newborn mice and zebrafish embryos, and upregulated matrix metallopeptidase ( MMP )-9 in endothelial cells and mast cells ( MCs ). Vascular lesions in newborn Adtrp -/- pups displayed accumulation of MCs , decreased extracellular matrix content, and deficient perivascular cell coverage. Wnt-pathway inhibition reversed the increased mmp9 in zebrafish embryos, demonstrating that mmp9 expression induced by Adtrp deficiency was downstream of canonical Wnt signaling. Conclusions Our studies demonstrate that ADTRP plays a major role in vascular development and function, most likely through expression in endothelial cells and/or perivascular cells of Wnt-regulated genes that control vascular stability and integrity.

Dataset Information

Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen.

Publications

Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen.

Similar Datasets

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