Published online before print April 24, 2003, doi: 10.1161/01.RES.0000073999.07698.33
© 2003 American Heart Association, Inc.
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FIZZ1/RELM
, a Novel Hypoxia-Induced Mitogenic Factor in Lung With Vasoconstrictive and Angiogenic Properties
From the Department of Anesthesiology and Critical Care Medicine (X.T., D.L., R.A.J.), Division of Cardiology, Department of Medicine (H.C.C.), Johns Hopkins University School of Medicine, Baltimore, Md.
Correspondence to Roger A. Johns, MD, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Blalock 1415, 600 N Wolfe St, Baltimore, MD 21287. E-mail Rajohns{at}jhmi.edu
Abstract
In a mouse chronic hypoxia model of pulmonary hypertension, we discovered a novel hypoxia-inducible gene in lung, FIZZ1/RELM
, first through a cDNA array analysis and then confirmed by RT-PCR. Western blot and immunohistochemistry revealed that its expression was induced by hypoxia only in lung. The hypoxia-upregulated gene expression was located in the pulmonary vasculature, bronchial epithelial cells, and type II pneumocytes. 3H-thymidine incorporation demonstrated that the recombinant protein stimulated rat pulmonary microvascular smooth muscle cell (RPSM) proliferation dose-dependently ranging from 3.3x10-9 to 3.3x10-8 mol/L. Therefore, we renamed this gene as hypoxia-induced mitogenic factor (HIMF). HIMF strongly activated Akt phosphorylation. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 (10 µmol/L) inhibited HIMF-activated Akt phosphorylation. It also inhibited HIMF-stimulated RPSM proliferation. Thus, the PI3K/Akt pathway, at least in part, mediates the proliferative effect of HIMF. Further studies showed that HIMF had angiogenic and vasoconstrictive properties. HIMF increased pulmonary arterial pressure and vascular resistance more potently than either endothelin-1 or angiotensin II.
Key Words: hypoxia-induced mitogenic factor • proliferation • vasoconstriction • angiogenesis • Akt
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