title: Hypoxia-induced mitogenic factor (FIZZ1/RELMα) induces endothelial cell apoptosis and subsequent interleukin-4-dependent pulmonary hypertension.
abstract: Pulmonary hypertension (PH) is characterized by elevated pulmonary artery pressure that leads to progressive right heart failure and ultimately death. Injury to endothelium and consequent wound repair cascades have been suggested to trigger pulmonary vascular remodeling, such as that observed during PH. The relationship between injury to endothelium and disease pathogenesis in this disorder remains poorly understood. We and others have shown that, in mice, hypoxia-induced mitogenic factor (HIMF, also known as FIZZ1 or RELMα) plays a critical role in the pathogenesis of lung inflammation and the development of PH. In this study, we dissected the mechanism by which HIMF and its human homolog resistin (hRETN) induce pulmonary endothelial cell (EC) apoptosis and subsequent lung inflammation-mediated PH, which exhibits many of the hallmarks of the human disease. Systemic administration of HIMF caused increases in EC apoptosis and interleukin (IL)-4-dependent vascular inflammatory marker expression in mouse lung during the early inflammation phase. In vitro, HIMF, hRETN, and IL-4 activated pulmonary microvascular ECs (PMVECs) by increasing angiopoietin-2 expression and induced PMVEC apoptosis. In addition, the conditioned medium from hRETN-treated ECs had elevated levels of endothelin-1 and caused significant increases in pulmonary vascular smooth muscle cell proliferation. Last, HIMF treatment caused development of PH that was characterized by pulmonary vascular remodeling and right heart failure in wild-type mice but not in IL-4 knockout mice. These data suggest that HIMF contributes to activation of vascular inflammation at least in part by inducing EC apoptosis in the lung. These events lead to subsequent PH.
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland; kkegan1@jhmi.edu.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Yamaji-Kegan
authors.affiliation: Division of Cardiology, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Eiki
authors.initials: E
authors.lastname: Takimoto
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Ailan
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Noah C
authors.initials: NC
authors.lastname: Weiner
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Lucas W
authors.initials: LW
authors.lastname: Meuchel
authors.affiliation: Divison of Allergy and Clinical Immunology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Alan E
authors.initials: AE
authors.lastname: Berger
authors.affiliation: Divison of Allergy and Clinical Immunology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Chris
authors.initials: C
authors.lastname: Cheadle
authors.affiliation: Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, Baltimore, Maryland;
authors.forename: Roger A
authors.initials: RA
authors.lastname: Johns
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D049109:Cell Proliferation; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D000860:Hypoxia / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000378:metabolism / Q000473:pathology
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; C413576:Retnla protein, mouse; D015847:Interleukin-4
keywords: T-helper type 2 inflammation; endothelial apoptosis; human resistin