Differential effects of PARP inhibition on vascular cell survival and ACAT-1 expression favouring atherosclerotic plaque stability.
OBJECTIVE
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.


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 H(2)O(2) 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.
Hans
Chetan P
CP
Department of Pharmacology and Experimental Therapeutics, LSU Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA.
Zerfaoui
Mourad
M
Naura
Amarjit S
AS
Catling
Andrew
A
Boulares
A Hamid
AH
D000101:Acetyl-CoA C-Acetyltransferase / Q000378:metabolism*; D000199:Actins / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D053148:Caspase 3 / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology*; D007653:Ketocholesterols / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000201:enzymology; D009336:Necrosis; D018384:Oxidative Stress / Q000187:drug effects; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000199:Actins; D001057:Apolipoproteins E; D004791:Enzyme Inhibitors; D007546:Isoquinolines; D007653:Ketocholesterols; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D013876:Thiophenes; D014409:Tumor Necrosis Factor-alpha; C475227:thieno(2,3-c)isoquinolin-5-one; D006861:Hydrogen Peroxide; C506641:Acat1 protein, mouse; D000101:Acetyl-CoA C-Acetyltransferase; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048670:MAP Kinase Kinase 4; C505409:Casp3 protein, mouse; D053148:Caspase 3; C003001:7-ketocholesterol