Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) Expression Is Decreased in Pulmonary Hypertension and Affects Endothelial Cell Growth
This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.
PPARγ 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 PPARγ has been described and PPARγ may function as a tumor suppressor gene, but little is known about the role of PPARγ 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 PPARγ expression in normal lungs, and in contrast, a reduced lung tissue PPARγ gene and protein expression in the lungs from patients with severe PH and loss of PPARγ expression in their complex vascular lesions. We show that fluid shear stress reduces PPARγ expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARγ (DN-PPARγ ECV304) form sprouts when placed in matrigel and that DN-PPARγ 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 PPARγ in endothelial cells and that loss of PPARγ expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.
- severe pulmonary hypertension
- peroxisome proliferator-activated receptor &ggr
- endothelial cell growth
- shear stress
- Received September 4, 2002.
- Revision received April 7, 2003.
- Accepted April 14, 2003.