Abstract
Objective
Prostacyclin (PGI2) is a potent ligand of peroxisome proliferator-activated receptor δ (PPARδ) that
regulates cell growth and differentiation. The aim of this study was to elucidate
how endogenous PGI2 overexpression affects the expressions of PPARδ and mitogen-activated protein kinases
(MAPKs) in the development of neointimal formation in experimental angioplasty with
adenovirus-mediated PGI2 synthase (Ad-PGIS) gene transfer.
Methods and results
In human aortic smooth muscle cells, protein blotting analysis showed that PGI2 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 PPARδ in the neointima of control vessels,
with no expression in uninjured vessels. The level of PPARδ expression was lower in
Ad-PGIS-treated arteries than in control vessels, with the PPARδ localized in the
neointima adjacent to endothelium. Staining of P-p38 MAPK showed a similar pattern
to PPARδ 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 PPARδ expression and inhibited neointimal formation
after balloon injury in accordance with the reduction in the phosphorylation of p38
MAPK.
Keywords
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References
- Peroxisome proliferator-activated receptors in the cardiovascular system.Br J Pharmacol. 2000; 129: 823-834
- The pleiotropic nature of the vascular PPAR gene regulatory pathway.Circ Res. 2001; 89: 935-937
- Pleiotropic actions of peroxisome proliferator-activated receptors in lipid metabolism and atherosclerosis.Arterioscler Thromb Vasc Biol. 2002; 22: 717-726
- Peroxisome proliferator-activated receptor δ is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells.J Biol Chem. 2002; 277: 11505-11512
- The vascular biology of atherosclerosis.Am J Med. 2003; 115: 55S-61S
- PPARα activators inhibit cytokine-induced vascular cell adhesion molecule-1 expression in human endothelial cells.Circulation. 1999; 99: 3125-3131
- Expression and function of PPARα in rat and human vascular smooth muscle cells.Circulation. 2000; 101: 1311-1318
- Pharmacology and endogenous roles of prostaglandin endoperoxides, thromboxane A2 and prostacyclin.Pharmacol Rev. 1979; 30: 293-331
- The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine.Nature. 1980; 299: 373-376
- Exogenous prostacyclin decreases vasoconstriction but not platelet thrombus deposition after arterial injury.J Am Coll Cardiol. 1993; 21: 488-492
- Inhibition of angiogenesis by non-steroidal anti-inflammatory drugs: insight into mechanisms and implications for cancer growth and ulcer healing.Nat Med. 1999; 5: 1418-1423
- Prostacyclin-dependent apoptosis mediated by PPAR delta.J Biol Chem. 2001; 276: 46260-46267
- Gene transfer of human prostacyclin synthase prevents neointimal formation after carotid balloon injury in rats.Stroke. 1999; 30: 419-426
- Prostacyclin synthase gene transfer accelerates reendothelialization and inhibits neointimal formation in rat carotid arteries after balloon injury.Arterioscler Thromb Vasc Biol. 1999; 19: 727-733
- Prostacyclin synthase gene transfer modulates cyclooxygenase-2-derived prostanoid synthesis and inhibits neointimal formation in rat balloon-injured arteries.Arterioscler Thromb Vasc Biol. 2002; 22: 256-262
- Prevention of arterial thrombosis by adenovirus-mediated transfer of cyclooxygenase gene.Circulation. 1996; 93: 10-17
- Catheter-based prostacyclin synthase gene transfer prevents in-stent restenosis in rabbit atheromatous arteries.Cardiovasc Res. 2004; 61: 177-185
- Docosahexaenoic acid, a peroxisome proliferator-activated receptor-alpha ligand, induces apoptosis in vascular smooth muscle cells by stimulation of p38 mitogen-activated protein kinase.Hypertension. 2000; 36: 851-858
- 15-Deoxy-12,14-prostaglandin J2 and thiazolidinediones activate the MEK/ERK pathway through phosphatidylinositol 3-kinase in vascular smooth muscle cells.J Biol Chem. 2001; 276: 48950-48955
- Activation of peroxisome proliferator-activated receptors (PPARs) by their ligands and protein kinase A activators.Mol Endocrinol. 2000; 14: 1962-1975
- Peroxisome proliferators-activated receptor delta is up-regulated during vascular lesion formation and promotes post-confluent cell proliferation in vascular smooth muscle cells.J Biol Chem. 2002; 277: 11505-11512
- Role of p38 mitogen-activated protein kinase in neointimal hyperplasia after vascular injury.Arterioscler Thromb Vasc Biol. 2000; 20: 2521-2526
- Prostaglandin I2 analogue, iloprost, down regulates mitogen-activated protein kinases of macrophages.J Surg Res. 1998; 76: 159-164
- Caldesmon-dependent switching between capillary endothelial cell growth and apoptosis through modulation of cell shape and contractility.Angiogenesis. 2003; 6: 55-64
- Colocalization prostacyclin (PGI2) synthase-caveolin-1 in endothelial cells and new roles for PGI2 in angiogenesis.Exp Cell Res. 2001; 266: 31-43
- Mechanosensing role of caveolae and caveolar constituents in human endothelial cells.J Cell Physiol. 2003; 197: 198-204
- Role of JNK, p38, and ERK in platelet-derived growth factor-induced vascular proliferation, migration, and gene expression.Arterioscler Thromb Vasc Biol. 2003; 23: 795-801
- A role for p38(MAPK)/HSP27 pathway in smooth muscle cell migration.J Biol Chem. 1999; 274: 24211-24219
- PPARs as therapeutic targets: reverse cardiology?.Science. 2003; 302: 406-407
Article info
Publication history
Published online: February 14, 2007
Accepted:
January 9,
2007
Received in revised form:
December 20,
2006
Received:
April 27,
2006
Identification
Copyright
© 2007 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.