Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen
Novel protein ADTRP regulates TFPI expression and function in human endothelial cells in normal conditions and in response to androgen
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DOI：
10.1182/blood-2011-05-355370
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发表时间：
2011-10-20
期刊：
影响因子：
20.3
通讯作者：
Lupu, Florea
中科院分区：
文献类型：
--
作者：
Lupu, Cristina;Zhu, Hua;Lupu, Florea
血栓形成和心血管疾病（CVD）是发病率和死亡率的主要原因。低雄激素与CVD/血栓形成的发生率较高相关。组织因子途径抑制剂（TFPI）是组织因子-因子VIIa（TF-FVIIa）依赖性FXA生成的主要抑制剂。由于内皮细胞（EC）功能障碍导致血管疾病与低EC相关TFPI，我们试图确定机制，调节TFPI的自然表达。NCBI的GEO微阵列的数据挖掘揭示了TFPI和由C6 ORF 105编码的未表征的蛋白质之间的强共表达，该蛋白质被预测为多跨度的、棕榈酰化的和雄激素响应的。我们证明，这种蛋白质调节天然和雄激素增强TFPI表达和活性在培养的EC，我们命名为雄激素依赖性TFPI调节蛋白（ADTRP）。我们证实ADTRP的表达和共定位与TFPI和小窝蛋白-1在EC。ADTRP-shRNA降低，而ADTRP的过表达增强TFPI mRNA和活性以及TF-FVIIa-FXa-TFPI与小窝蛋白-1的共定位。成像和Triton X-114提取证实TFPI和ADTRP与脂筏/小窝相关。二氢睾酮上调TFPI和ADTRP表达，并以ADTRP和小窝蛋白-1依赖性方式增加TFPI对FXa的抑制。我们的结论是，ADTRP依赖性上调TFPI的表达和活性的雄激素代表了一种新的机制，增加抗凝保护的内皮细胞。（血。2011;118（16）：4463-4471）
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 upregulation of TFPI expression and activity by androgen represents a novel mechanism of increasing the anticoagulant protection of the endothelium. (Blood. 2011;118(16):4463-4471)