Differential Roles of PARP‐1 in oxidants‐mediated cell death in an in vitro model mimicking atherosclerotic plaque dynamics: implication in atherosclerosis

Abstract

The present study intended to explore the differential roles of PARP-1 inhibition (pharmacologically and/or gene deletion) in cell death in response to pro-inflammatory agents 7-ketocholestrol (7-KC), H2O2 and TNF in an in-vitro system mimicking atherosclerotic plaque dynamics. H2O2 or TNF treatment induced a dose and time dependent death in an ex-vivo generated foam cells (FC), SMC (smooth muscle cells) and endothelial (HUVEC) cells with varying degrees of apoptosis and/or necrosis. PARP-1 inhibition protected against both forms of death in all cell types against these agents. At higher doses of H2O2, necrosis was the predominant form of cell death in PARP-1 expressing cells; PARP-1 inhibition switched the mode of cell death from necrosis to caspase-3-dependent apoptosis. Similarly, PARP-1 inhibition provided protection to SMC cells against 7-KC. In contrast, PARP-1 inhibition, not only did not confer protection to FC against 7-KC, it caused a significant sensitization to this agent. Such increased-cell sensitivity to 7-KC may be associated with an increase in toxic free cholesterol in these cells due to a potential defect in FC maturation. Our data suggests that PARP-1 plays different roles within atherosclerotic plaques and that its inhibition provides conditions consistent with plaque stability (i.e. protecting SMC and EC and promoting death of lipid-laden FC). Support: 1P20RR18766 and HL072889 to HB.