title: Targeting activation of specific NF-κB subunits prevents stress-dependent atherothrombotic gene expression.
abstract: Psychosocial stress has been shown to be a contributing factor in the development of atherosclerosis. Although the underlying mechanisms have not been elucidated entirely, it has been shown previously that the transcription factor nuclear factor-κB (NF-κB) is an important component of stress-activated signaling pathway. In this study, we aimed to decipher the mechanisms of stress-induced NF-κB-mediated gene expression, using an in vitro and in vivo model of psychosocial stress. Induction of stress led to NF-κB-dependent expression of proinflammatory (tissue factor, intracellular adhesive molecule 1 [ICAM-1]) and protective genes (manganese superoxide dismutase [MnSOD]) via p50, p65 or cRel. Selective inhibition of the different subunits and the respective kinases showed that inhibition of cRel leads to the reduction of atherosclerotic lesions in apolipoprotein(-/-) (ApoE(-/-)) mice via suppression of proinflammatory gene expression. This observation may therefore provide a possible explanation for ineffectiveness of antioxidant therapies and suggests that selective targeting of cRel activation may provide a novel approach for the treatment of stress-related inflammatory vascular disease.
authors.affiliation: Department of Medicine I and Clinical Chemistry, University of Heidelberg, Heidelberg, Germany.
authors.forename: Zdenka
authors.initials: Z
authors.lastname: Djuric
authors.forename: Muhammed
authors.initials: M
authors.lastname: Kashif
authors.forename: Thomas
authors.initials: T
authors.lastname: Fleming
authors.forename: Sajjad
authors.initials: S
authors.lastname: Muhammad
authors.forename: David
authors.initials: D
authors.lastname: Piel
authors.forename: Rüdiger
authors.initials: R
authors.lastname: von Bauer
authors.forename: Florian
authors.initials: F
authors.lastname: Bea
authors.forename: Stephan
authors.initials: S
authors.lastname: Herzig
authors.forename: Martin
authors.initials: M
authors.lastname: Zeier
authors.forename: Marina
authors.initials: M
authors.lastname: Pizzi
authors.forename: Berend
authors.initials: B
authors.lastname: Isermann
authors.forename: Markus
authors.initials: M
authors.lastname: Hecker
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaninger
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter P
authors.initials: PP
authors.lastname: Nawroth
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism / Q000494:pharmacology; D050197:Atherosclerosis / Q000150:complications / Q000235:genetics* / Q000523:psychology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism*; D009638:Norepinephrine; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D021122:Protein Subunits / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013315:Stress, Psychological / Q000150:complications / Q000235:genetics*; D013927:Thrombosis / Q000150:complications / Q000235:genetics* / Q000523:psychology
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D009638:Norepinephrine; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D021122:Protein Subunits; D020569:Proto-Oncogene Proteins c-rel