Cardiovascular Research Advance Access originally published online on January 31, 2008
Cardiovascular Research 2008 78(3):429-439; doi:10.1093/cvr/cvn018
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability
Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA
* Corresponding Author. Tel: +1 504 568 2304; fax: +1 504 568 2361. E-mail address: hboulr{at}lsuhsc.edu
Aims: The aim of this study was to take a combination of animal and cell culture approaches to examine the individual responses of vascular cells to varying inflammatory factors in order to gain insights on the mechanism(s) by which poly(ADP-ribose) polymerase (PARP) inhibition promotes factors of plaque stability.
Methods and results: Apolipoprotein (ApoE–/–) mice fed a high-fat diet were used as a model of atherosclerosis. Primary endothelial cells, smooth muscle cells (SMCs), and ex-vivo generated foam cells (FCs) were used in our in vitro studies. PARP inhibition significantly decreased the markers of oxidative stress and caspase-3 activation and increased smooth muscle actin within plaques from ApoE–/– mice fed a high-fat diet. PARP inhibition protected against apoptosis and/or necrosis in SMCs and endothelial cells in response to H2O2 or tumour necrosis factor (TNF). Remarkably, PARP inhibition in FCs resulted in significant sensitization to 7-ketocholesterol (7-KC) by increasing cellular-toxic-free cholesterol, potentially through a down-regulation of acyl-CoA:cholesterol acyltransferase-1 (ACAT-1) expression. 7-KC induced necrosis exclusively in endothelial cells, which was, surprisingly, unaffected by PARP inhibition indicating that PARP inhibition does not prevent all forms of necrotic cell death. In SMCs, PARP-1 inhibition by gene deletion conferred protection against 7-KC or TNF, potentially by reducing caspase-3-like activation, preventing induction of c-Jun N-terminal protein kinase phosphorylation, and inducing extracellular signal-regulated kinase phosphorylation independently of PARP classical enzymatic activity.
Conclusions: These data present PARP-1 as an important player in the death of cells constituting atherosclerotic plaques contributing to plaque dynamics. PARP inhibition may be a protective, a neutral, or a sensitizing factor. Additionally, PARP-1 may be a novel factor that can alter lipid metabolism. These novel functions of PARP not only challenge the current understanding of the role of the enzyme in cell death but also provide insights on the intricate contribution of PARP in cellular responses to predominant inflammatory factors within atherosclerotic plaques, presenting additional evidence for the viability of PARP inhibition as a therapeutic strategy for atherosclerosis.
KEYWORDS Atherosclerosis; Apoptosis; Necrosis; PARP-1; Lipid metabolism
Time for primary review: 21 days
CiteULike 
Connotea 
Del.icio.us What's this?
Related articles in Cardiovasc Res:
- Targeting the prevention of plaque rupture as a new strategy for prevention of acute arterial cardiovascular events
- Marcel Levi and Erik Stroes
Cardiovasc Res 2008 78: 407-408.[Extract] [FREE Full Text]
Related Article
- Targeting the prevention of plaque rupture as a new strategy for prevention of acute arterial cardiovascular events
- Marcel Levi and Erik Stroes
Cardiovasc Res 2008 78: 407-408.[Extract] [Full Text] [PDF]
This article has been cited by other articles:
|
|
 |
|
  C. P. Hans, M. Zerfaoui, A. S. Naura, D. Troxclair, J. P. Strong, K. Matrougui, and A. H. Boulares Thieno[2,3-c]Isoquinolin-5-one, a Potent Poly(ADP-Ribose) Polymerase Inhibitor, Promotes Atherosclerotic Plaque Regression in High-Fat Diet-Fed Apolipoprotein E-Deficient Mice: Effects on Inflammatory Markers and Lipid Content J. Pharmacol. Exp. Ther., April 1, 2009; 329(1): 150 - 158. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Levi and E. Stroes Targeting the prevention of plaque rupture as a new strategy for prevention of acute arterial cardiovascular events Cardiovasc Res, June 1, 2008; 78(3): 407 - 408. [Full Text] [PDF]
|
|