Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)–Induced Pulmonary Hypertension
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY(2016)
摘要
Objective 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 resistin-like molecule-) 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. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1(+/+)) and HIF-1 heterozygous null (HIF-1(+/-)) mice. HIMF-induced PH was significantly diminished in HIF-1(+/-) mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1 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-, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1 and, at least to some extent, on nuclear factor B. Conclusions Our results suggest that HIF-1 is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule- 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, vascular endothelial growth factor-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.
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关键词
hypertension,pulmonary,hypoxia-inducible factor 1,interleukins,macrophages,resistin-like molecule
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