Hypoxia-inducible factor 1α is a critical downstream mediator for hypoxia-induced mitogenic factor (FIZZ1/RELMα)–induced pulmonary hypertension
RA Johns, E Takimoto, LW Meuchel… - … , and vascular biology, 2016 - Am Heart Assoc
RA Johns, E Takimoto, LW Meuchel, E Elsaigh, A Zhang, NM Heller, GL Semenza…
Arteriosclerosis, thrombosis, and vascular biology, 2016•Am Heart AssocObjective—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-β) 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 …
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-β) 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 …
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-β) 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-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 vascular endothelial growth factor-A–vascular endothelial growth factor 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, significantly increased interleukin (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.
Conclusions
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 resistin-like molecule-β 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.
Am Heart Assoc