Peroxisome proliferator-activated receptor type gamma (PPARγ) is a subgroup of the PPAR transcription factor family. Recent studies indicate that loss of PPARγ is associated with the development of pulmonary hypertension (PH). We hypothesized that the endothelial dysfunction associated with PPARγ inhibition may play an important role in the disease process by altering cellular gene expression and signaling cascades. We utilized microarray analysis to determine if PPARγ inhibition induced changes in gene expression in pulmonary arterial endothelial cells (PAEC). We identified 100 genes and expressed sequence tags (ESTs) that were upregulated by >1.5-fold and 21 genes and ESTs that were downregulated by >1.3-fold (P < 0.05) by PPARγ inhibition. The upregulated genes can be broadly classified into four functional groups: cell cycle, angiogenesis, ubiquitin system, and zinc finger proteins. The genes with the highest fold change in expression: hyaluronan-mediated motility receptor (HMMR), VEGF receptor 2 (Flk-1), endothelial PAS domain protein 1 (EPAS1), basic fibroblast growth factor (FGF-2), and caveolin-1 in PAEC were validated by real time RT-PCR. We further validated the upregulation of HMMR, Flk-1, FGF2, and caveolin-1 by Western blot analysis. In keeping with the microarray results, PPARγ inhibition led to re-entry of cell cycle at G1/S phase and cyclin C upregulation. PPARγ inhibition also exacerbated VEGF-induced endothelial barrier disruption. Finally we confirmed the downregulation of PPARγ and the upregulation of HMMR, Flk-1, FGF2, and Cav-1 proteins in the peripheral lung tissues of an ovine model of PH. In conclusion, we have identified an array of endothelial genes modulated by attenuated PPARγ signaling that may play important roles in the development of PH.
|Original language||English (US)|
|Number of pages||13|
|State||Published - Jan 1 2009|
- Cell signaling
- Peroxisome proliferator-activated receptor
ASJC Scopus subject areas