Human Gene Set: GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLACK_DN


Standard name GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLACK_DN
Systematic name M4397
Brief description Genes from the black module which are dn-regulated in HAEC cells (primary aortic endothelium) after exposure to the oxidized 1-palmitoyl-2-arachidonyl-sn-3-glycerophosphorylcholine (oxPAPC).
Full description or abstract Oxidized phospholipids are thought to promote atherogenesis by stimulating endothelial cells (ECs) to produce inflammatory cytokines, such as IL-8. In studies with mouse models, we previously demonstrated that genetic variation in inflammatory responses of endothelial cells to oxidized lipids contributes importantly to atherosclerosis susceptibility. We now show that similar variations occur in cultured aortic ECs derived from multiple heart transplant donors. These variations were stably maintained between passages and, thus, reflect either genetic or epigenetic regulatory differences. Expression array analysis of aortic EC cultures derived from 12 individuals revealed that >1,000 genes were regulated by oxidized phospholipids. We have used the observed variations in the sampled population to construct a gene coexpression network comprised of 15 modules of highly connected genes. We show that several identified modules are significantly enriched in genes for known pathways and confirm a module enriched for unfolded protein response (UPR) genes using siRNA and the UPR inducer tunicamycin. On the basis of the constructed network, we predicted that a gene of unknown function (MGC4504) present in the UPR module is a target for UPR transcriptional activator ATF4. Our data also indicate that IL-8 is present in the UPR module and is regulated, in part, by the UPR. We validate these by using siRNA. In conclusion, we show that interindividual variability can be used to group genes into pathways and predict gene-gene regulatory relationships, thus identifying targets potentially involved in susceptibility to common diseases such as atherosclerosis.
Collection C2: Curated
      CGP: Chemical and Genetic Perturbations
Source publication Pubmed 16912112   Authors: Gargalovic PS,Imura M,Zhang B,Gharavi NM,Clark MJ,Pagnon J,Yang WP,He A,Truong A,Patel S,Nelson SF,Horvath S,Berliner JA,Kirchgessner TG,Lusis AJ
Exact source Table 1S: module=black & fold change < 0.667
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Source species Homo sapiens
Contributed by Arthur Liberzon (MSigDB Team)
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identifier namespace		 AFFY_HG_U133
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