Transcription regulation of TNF-alpha-early response genes by poly(ADP-ribose) polymerase-1 in murine heart endothelial cells.
Poly(ADP-ribose) polymerase-1 (PARP-1) has been involved in endothelial cell dysfunction associated with various pathophysiological conditions. The intrinsic mechanism of PARP-1-mediated endothelial cell dysfunction could be related to PARP-1 overactivation, NAD(+) consumption and ATP depletion. An alternative way could involve transcription regulation. By using high-density microarrays, we examined early tumor necrosis factor alpha (TNF-alpha)-stimulated gene expression profiles in PARP-1(+/+) and PARP-1(-/-) murine heart endothelial cells. TNF-alpha modulated a significant number of genes in both cell types. We have identified a set of genes whose expression in response to TNF-alpha is modulated by PARP-1, whereas the expression of others is PARP-1-independent. Up-regulation of several genes involved in the inflammatory response is hampered in the absence of PARP-1. Moreover, NF-kappaB-dependent transcriptional activation is partially inhibited in PARP-1(-/-) compared to PARP-1(+/+) cells. However, we found that PARP-1 might also silence transcription of several NF-kappaB target genes. Overall, our results show that PARP-1 is regulating the expression of genes by the endothelial cells both in a positive and a negative fashion, with the final effects depending on the gene. Individual studies of these genes are now necessary to clarify the intrinsic mechanism by which PARP-1 is controlling transcription and thereby finding out different therapeutic approaches involving PARP-1.
Carrillo
Ana
A
Transplant Unit, University Hospital Virgen de la Arrixaca, Murcia, Spain.
Monreal
Yolanda
Y
Ramírez
Pablo
P
Marin
Luis
L
Parrilla
Pascual
P
Oliver
Francisco Javier
FJ
Yélamos
José
J
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D019040:E-Selectin / Q000235:genetics; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D020868:Gene Silencing / Q000187:drug effects; D017781:Genes, Immediate-Early / Q000235:genetics*; D007249:Inflammation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology; D016328:NF-kappa B / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D011065:Poly(ADP-ribose) Polymerases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
D018925:Chemokines; D019040:E-Selectin; D016328:NF-kappa B; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; D011065:Poly(ADP-ribose) Polymerases