| First Author | Johns RA | Year | 2016 |
| Journal | Arterioscler Thromb Vasc Biol | Volume | 36 |
| Issue | 1 | Pages | 134-44 |
| PubMed ID | 26586659 | Mgi Jnum | J:242379 |
| Mgi Id | MGI:5905104 | Doi | 10.1161/ATVBAHA.115.306710 |
| Citation | Johns RA, et al. (2016) Hypoxia-Inducible Factor 1alpha Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMalpha)-Induced Pulmonary Hypertension. Arterioscler Thromb Vasc Biol 36(1):134-44 |
| abstractText | 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-beta) 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-1alpha(+/+)) and HIF-1alpha heterozygous null (HIF-1alpha(+/-)) mice. HIMF-induced PH was significantly diminished in HIF-1alpha(+/-) mice and was accompanied by a dysregulated vascular endothelial growth factor-A-vascular endothelial growth factor receptor 2 pathway. HIF-1alpha 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-beta, significantly increased interleukin (IL)-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1alpha and, at least to some extent, on nuclear factor kappaB. CONCLUSIONS: Our results suggest that HIF-1alpha is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human resistin-like molecule-beta 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. |
