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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/L582    most recent 90526.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Angelini, D. J. Articles by Johns, R. A. Search for Related Content PubMed PubMed Citation Articles by Angelini, D. J. Articles by Johns, R. A.

Hypoxia-induced mitogenic factor (HIMF/FIZZ1/RELM) induces the vascular and hemodynamic changes of pulmonary hypertension

¹Department of Anesthesiology and Critical Care Medicine, ²Division of Cardiology, ³Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland

Submitted 16 October 2008 ; accepted in final form 5 January 2009

Pulmonary hypertension (PH) is a serious disease of multiple etiologies mediated by hypoxia, immune stimuli, and elevated pulmonary pressure that leads to vascular thickening and eventual right heart failure. In a chronic hypoxia model of PH, we previously reported the induction of a novel pleiotropic cytokine, hypoxia-induced mitogenic factor (HIMF), that exhibits mitogenic, vasculogenic, contractile, and chemokine properties during PH-associated vascular remodeling. To examine the role of HIMF in hypoxia-induced vascular remodeling, we performed in vivo knockdown of HIMF using short hairpin RNA directed at rat HIMF in the chronic hypoxia model of PH. Knockdown of HIMF partially blocked increases in mean pulmonary artery pressure, pulmonary vascular resistance, right heart hypertrophy, and vascular remodeling caused by chronic hypoxia. To demonstrate a direct role for HIMF in the mechanism of PH development, we performed HIMF-gene transfer into the lungs of rats using a HIMF-expressing adeno-associated virus (AAV). AAV-HIMF alone caused development of PH similar to that of chronic hypoxia with increased mean pulmonary artery pressure and pulmonary vascular resistance, right heart hypertrophy, and neomuscularization and thickening of small pulmonary arterioles. The findings suggest that HIMF represents a critical cytokine-like growth factor in the development of PH.

vascular remodeling; hypoxia; T-helper 2

This article has been cited by other articles:

				C. Fan, Q. Su, Y. Li, L. Liang, D. J. Angelini, W. B. Guggino, and R. A. Johns Hypoxia-induced mitogenic factor/FIZZ1 induces intracellular calcium release through the PLC-IP3 pathway Am J Physiol Lung Cell Mol Physiol, August 1, 2009; 297(2): L263 - L270. [Abstract] [Full Text] [PDF]