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
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to AtherosclerosisAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
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.
