Prostacyclin synthase gene transfer inhibits neointimal formation by suppressing PPAR delta expression.
OBJECTIVE
Prostacyclin (PGI(2)) is a potent ligand of peroxisome proliferator-activated receptor delta (PPAR delta) that regulates cell growth and differentiation. The aim of this study was to elucidate how endogenous PGI(2) overexpression affects the expressions of PPAR delta and mitogen-activated protein kinases (MAPKs) in the development of neointimal formation in experimental angioplasty with adenovirus-mediated PGI(2) synthase (Ad-PGIS) gene transfer.


RESULTS
In human aortic smooth muscle cells, protein blotting analysis showed that PGI(2) overproduction decreased the levels of phosphorylated p38 MAPK (P-p38 MAPK) (2.0-fold versus 0.83-fold relative to control). Immunohistochemical analysis in balloon-injured arteries revealed diffuse expression of PPAR delta in the neointima of control vessels, with no expression in uninjured vessels. The level of PPAR delta expression was lower in Ad-PGIS-treated arteries than in control vessels, with the PPAR delta localized in the neointima adjacent to endothelium. Staining of P-p38 MAPK showed a similar pattern to PPAR delta among the three groups. Morphometric analysis at day 14 revealed that Ad-PGIS reduced the intima-to-media ratio by up to 59%.


CONCLUSIONS
Ad-PGIS gene transfer reduced PPAR delta expression and inhibited neointimal formation after balloon injury in accordance with the reduction in the phosphorylation of p38 MAPK.
Imai
Hajime
H
Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
Numaguchi
Yasushi
Y
Ishii
Masakazu
M
Kubota
Ryuji
R
Yokouchi
Kazuhiko
K
Ogawa
Yasuhiro
Y
Kondo
Takahisa
T
Okumura
Kenji
K
Murohara
Toyoaki
T
D000256:Adenoviridae / Q000235:genetics; D017130:Angioplasty / Q000009:adverse effects; D000818:Animals; D001011:Aorta / Q000166:cytology / Q000378:metabolism; D020212:Carotid Artery Injuries / Q000235:genetics / Q000503:physiopathology; D002478:Cells, Cultured; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D011464:Epoprostenol / Q000378:metabolism; D018014:Gene Transfer Techniques; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000502:physiology*; D047494:PPAR delta / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017539:Tunica Intima / Q000503:physiopathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D047494:PPAR delta; D003577:Cytochrome P-450 Enzyme System; D011464:Epoprostenol; D048051:p38 Mitogen-Activated Protein Kinases; D019746:Intramolecular Oxidoreductases; C022461:prostacyclin synthetase