• Roger A Johns, Eiki Takimoto, Lucas W Meuchel, Esra Elsaigh, Ailan Zhang, Nicola M Heller, Gregg L Semenza, and Kazuyo Yamaji-Kegan.
• Department of Anesthesiology and Critical Care Medicine (R.A.J., L.W.M., E.E., A.Z., N.M.H., K.Y.-K.), the Division of Cardiology (E.T.), and Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, Radiation Oncology, and Biological Chemistry (G.L.S.), McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins Medical Institutions, Baltimore, MD.
• Arterioscler. Thromb. Vasc. Biol. 2016 Jan 1; 36 (1): 134-44.

ObjectivePulmonary 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 ResultsIn 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.ConclusionsOur 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.© 2015 American Heart Association, Inc.

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