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Updated: Sep 26, 2026
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Published on: May 11, 2015
Peroxisome proliferator-activated receptor gamma (PPARgamma) expression is decreased in pulmonary hypertension and
Shingo Ameshima1, Heiko Golpon, Carlyne D Cool
1Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colo, USA.
Abstract:
PPARgamma 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 PPARgamma has been described and PPARgamma may function as a tumor suppressor gene, but little is known about the role of PPARgamma 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 PPARgamma expression in normal lungs, and in contrast, a reduced lung tissue PPARgamma gene and protein expression in the lungs from patients with severe PH and loss of PPARgamma expression in their complex vascular lesions. We show that fluid shear stress reduces PPARgamma expression in ECV304 endothelial cells, that ECV304 cells that stably express dominant-negative PPARgamma (DN-PPARgamma ECV304) form sprouts when placed in matrigel and that DN-PPARgamma 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 PPARgamma in endothelial cells and that loss of PPARgamma expression characterizes an abnormal, proliferating, apoptosis-resistant endothelial cell phenotype.
Insights
Peroxisome proliferator-activated receptor gamma (PPARgamma) loss in lung endothelial cells drives vascular remodeling in pulmonary hypertension. Reduced PPARgamma expression promotes abnormal cell proliferation and resistance to apoptosis, contributing to disease progression.
Area of Science:
- Endocrinology
- Molecular Biology
- Cardiovascular Research
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with known antiproliferative and proapoptotic functions.
- Its role in vascular remodeling, particularly in pulmonary hypertension (PH), remains largely unexplored.
- Severe PH is characterized by pathological vascular remodeling in the lungs, leading to increased pulmonary arterial pressure.
Purpose of the Study:
- To investigate the role of PPARgamma in the vascular remodeling associated with severe pulmonary hypertension.
- To determine the effect of fluid shear stress on PPARgamma expression in endothelial cells.
- To elucidate the contribution of PPARgamma loss to the development of pulmonary vascular lesions.
Main Methods:
- Quantitative analysis of PPARgamma gene and protein expression in normal lungs versus lungs from severe PH patients.
- In vitro studies using ECV304 endothelial cells to assess the impact of fluid shear stress on PPARgamma expression.
- Experimental models involving stable expression of dominant-negative PPARgamma (DN-PPARgamma) in endothelial cells and subsequent in vivo studies in nude mice.
Main Results:
- PPARgamma is ubiquitously expressed in normal lung tissue but significantly reduced in lungs from patients with severe PH.
- Reduced PPARgamma expression and loss of expression were observed in the complex vascular lesions of severe PH.
- Fluid shear stress was found to decrease PPARgamma expression in endothelial cells.
- Endothelial cells expressing DN-PPARgamma exhibited increased sprouting and formed lumen-obliterating lung vascular lesions after injection in mice.
Conclusions:
- Loss of PPARgamma expression in lung endothelial cells is a hallmark of severe pulmonary hypertension.
- Decreased PPARgamma expression, induced by factors like fluid shear stress, contributes to an abnormal, proliferating, and apoptosis-resistant endothelial cell phenotype.
- PPARgamma plays a critical role in preventing pathological vascular remodeling in the pulmonary vasculature.
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