Peroxisome proliferator-activated receptor gamma (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth

Shingo Ameshima, Heiko Golpon, Carlyne D. Cool, Daniel Chan, R. William Vandivier, Shyra J. Gardai, Marilee Wick, Raphael A. Nemenoff, Mark W. Geraci, Norbert F. Voelkel

Research output: Contribution to journalArticle

206 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1162-1169
Number of pages8
JournalCirculation research
Volume92
Issue number10
DOIs
StatePublished - May 30 2003

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Keywords

  • Apoptosis
  • Endothelial cell growth
  • Peroxisome proliferator-activated receptor γ
  • Severe pulmonary hypertension
  • Shear stress

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Ameshima, S., Golpon, H., Cool, C. D., Chan, D., Vandivier, R. W., Gardai, S. J., Wick, M., Nemenoff, R. A., Geraci, M. W., & Voelkel, N. F. (2003). Peroxisome proliferator-activated receptor gamma (PPARγ) expression is decreased in pulmonary hypertension and affects endothelial cell growth. Circulation research, 92(10), 1162-1169. https://doi.org/10.1161/01.RES.0000073585.50092.14