Published online before print April 24, 2003, doi: 10.1161/01.RES.0000073585.50092.14
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© 2003 American Heart Association, Inc.
Integrative Physiology |
Peroxisome Proliferator-Activated Receptor Gamma (PPAR
) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth
From the Pulmonary Hypertension Center (S.A., N.F.V., R.W.V., S.J.G., M.W.G.), Division of Renal Medicine (R.A.N., M.W.), Cancer Center (D.C., R.A.N., M.W.G.), and Department of Pathology (C.D.C.), University of Colorado Health Sciences Center, Denver, Colo; National Jewish Research Center (R.W.V., S.J.G.), Denver, Colo; Pulmonary Division (H.G.), Universitätsklinik Magdeburg, Germany.
Correspondence to Norbert F. Voelkel, MD, Division of Pulmonary Sciences and Critical Care Medicine, 4200 East Ninth Ave, C272, Denver, CO 80262. E-mail Norbert.Voelkel{at}uchsc.edu
PPAR
is a member of a family of nuclear receptors/ligand–dependent transcription factors, which bind to hormone response elements on target gene promoters. An antiproliferative and proapoptotic action profile of PPAR has been described and PPAR may function as a tumor suppressor gene, but little is known about the role of PPAR in vascular remodeling. One group of human diseases that shows impressive vascular remodeling exclusively in the lungs is the group of severe pulmonary hypertensive disorders, which is characterized by complex, endothelial cell–proliferative lesions of lung precapillary arterioles composed of clusters of phenotypically altered endothelial cells that occlude the vessel lumen and contribute to the elevation of the pulmonary arterial pressure and reduce local lung tissue blood flow. In the present study, we report the ubiquitous PPAR expression in normal lungs, and in contrast, a reduced lung tissue PPAR gene and protein expression in the lungs from patients with severe PH and loss of PPAR expression in their complex vascular lesions. We show that fluid shear stress reduces PPAR expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPAR (DN-PPAR ECV304) form sprouts when placed in matrigel and that DN-PPAR ECV304 cells, after tail vein injection in nude mice, form lumen-obliterating lung vascular lesions. We conclude that fluid shear stress decreases the expression of PPAR in endothelial cells and that loss of PPAR expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.
Key Words: severe pulmonary hypertension • peroxisome proliferator-activated receptor &ggr • endothelial cell growth • apoptosis • shear stress
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