Effect of PPARγ inhibition on pulmonary endothelial cell gene expression

Gene profiling in pulmonary hypertension

Jing Tian, Anita Smith, John Nechtman, Robert Podolsky, Saurabh Aggarwal, Connie Snead, Sanjiv Kumar, Manal Elgaish, Peter Oishi, Agnes Göerlach, Sohrab Fratz, John Hess, John D. Catravas, Alexander Dmitriyevich Verin, Jeffrey R. Fineman, Jin-Xiong She, Stephen Matthew Black

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

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 languageEnglish (US)
Pages (from-to)48-60
Number of pages13
JournalPhysiological Genomics
Volume40
Issue number1
DOIs
StatePublished - Jan 1 2009

Fingerprint

PPAR gamma
Gene Expression Profiling
Pulmonary Hypertension
Endothelial Cells
Lung
Fibroblast Growth Factor 2
Genes
Caveolin 1
Up-Regulation
Expressed Sequence Tags
Cyclin C
Cell Cycle
Down-Regulation
Gene Expression
Vascular Endothelial Growth Factor Receptor-2
Zinc Fingers
G1 Phase
Microarray Analysis
Ubiquitin
S Phase

Keywords

  • Cell signaling
  • Microarray
  • Peroxisome proliferator-activated receptor

ASJC Scopus subject areas

  • Physiology
  • Genetics

Cite this

Effect of PPARγ inhibition on pulmonary endothelial cell gene expression : Gene profiling in pulmonary hypertension. / Tian, Jing; Smith, Anita; Nechtman, John; Podolsky, Robert; Aggarwal, Saurabh; Snead, Connie; Kumar, Sanjiv; Elgaish, Manal; Oishi, Peter; Göerlach, Agnes; Fratz, Sohrab; Hess, John; Catravas, John D.; Verin, Alexander Dmitriyevich; Fineman, Jeffrey R.; She, Jin-Xiong; Black, Stephen Matthew.

In: Physiological Genomics, Vol. 40, No. 1, 01.01.2009, p. 48-60.

Research output: Contribution to journalArticle

Tian, J, Smith, A, Nechtman, J, Podolsky, R, Aggarwal, S, Snead, C, Kumar, S, Elgaish, M, Oishi, P, Göerlach, A, Fratz, S, Hess, J, Catravas, JD, Verin, AD, Fineman, JR, She, J-X & Black, SM 2009, 'Effect of PPARγ inhibition on pulmonary endothelial cell gene expression: Gene profiling in pulmonary hypertension', Physiological Genomics, vol. 40, no. 1, pp. 48-60. https://doi.org/10.1152/physiolgenomics.00094.2009
Tian, Jing ; Smith, Anita ; Nechtman, John ; Podolsky, Robert ; Aggarwal, Saurabh ; Snead, Connie ; Kumar, Sanjiv ; Elgaish, Manal ; Oishi, Peter ; Göerlach, Agnes ; Fratz, Sohrab ; Hess, John ; Catravas, John D. ; Verin, Alexander Dmitriyevich ; Fineman, Jeffrey R. ; She, Jin-Xiong ; Black, Stephen Matthew. / Effect of PPARγ inhibition on pulmonary endothelial cell gene expression : Gene profiling in pulmonary hypertension. In: Physiological Genomics. 2009 ; Vol. 40, No. 1. pp. 48-60.
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AU - Podolsky, Robert

AU - Aggarwal, Saurabh

AU - Snead, Connie

AU - Kumar, Sanjiv

AU - Elgaish, Manal

AU - Oishi, Peter

AU - Göerlach, Agnes

AU - Fratz, Sohrab

AU - Hess, John

AU - Catravas, John D.

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