Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension.
Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)-Induced Pulmonary Hypertension.
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DOI：
10.1161/atvbaha.115.306710
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发表时间：
2016-01
期刊：
影响因子：
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通讯作者：
Yamaji-Kegan K
中科院分区：
文献类型：
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作者：
Johns RA;Takimoto E;Meuchel LW;Elsaigh E;Zhang A;Heller NM;Semenza GL;Yamaji-Kegan K
肺动脉高压（PH）的特征是肺血管阻力进行性升高，右心室衰竭，最终死亡。我们已经证明，在啮齿动物中，缺氧诱导的有丝分裂因子（HIMF;也称为FIZZ 1或RELMα）通过引发肺血管炎症引起PH。我们假设缺氧诱导因子-1（HIF-1）是PH发展过程中HIMF的关键下游信号介质。在这项研究中，我们比较了野生型（HIF-1α+/+）和HIF-1α杂合无效（HIF-1 α+/−）小鼠中HIF诱导的肺血管重塑和PH发展的程度。在HIF-1α+/−小鼠中，HIF诱导的PH显著减少，并伴有VEGF-A-VEGF受体2通路失调。HIF-1α在HIMF诱导的骨髓细胞迁移和血管形成中起关键作用。此外，HIMF及其人类同源物抵抗素样分子-β（RELMβ）通过依赖于HIF-1α和至少在一定程度上依赖于核因子κB的机制显著增加巨噬细胞和肺驻留细胞中的IL-6。我们的研究结果表明，HIF-1α是HIF诱导的肺血管重构和PH发展的关键下游转录因子。重要的是，HIMF和人RELMβ均显著增加肺驻留细胞中的IL-6，并增加小鼠肺中表达IL-6的巨噬细胞的血管周围积聚。这些数据表明，HIMF可以诱导HIF-1，VEGF-A和白细胞介素-6，这是缺氧炎症和PH病理生理学的关键介质。
Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.