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.
Highlights
Atherosclerosis, despite intensive research efforts, remains a major health burden in the postmodern Western society
Activation of the redox-sensitive transcriptional factor nuclear factor-κB (NF-κB) is believed to be an important component of the cascade of events triggered by psychosocial stress, leading to inflammation, thrombosis and vascular damage [3,4,5,6,7,8,9,10,11]
Upon stimulation, the ICAM-1 promoter was occupied by p50, p65 and cRel, the tissue factor (TF)
Summary
Atherosclerosis, despite intensive research efforts, remains a major health burden in the postmodern Western society. Psychosocial stress has been shown to be an independent risk factor for cardiovascular disease [1] amendable by intervention [2], but the underlying mechanisms which lead to atherosclerosis remain unclear. Activation of the redox-sensitive transcriptional factor nuclear factor-κB (NF-κB) is believed to be an important component of the cascade of events triggered by psychosocial stress, leading to inflammation, thrombosis and vascular damage [3,4,5,6,7,8,9,10,11]. NF-κB subunits are expressed ubiquitously and can be activated by a wide range of stimuli, such as reactive oxygen species (ROS), cytokines, infection and DNA damage; their actions are regulated in a cell- and stimulus-specific manner, leading to a diverse spectrum of effects [12]. A potential explanation for this discrepancy might be provided by the observation that members of the NF-κB family orchestrate gene clusters required for the resolution of inflammation [20,21,22,23], for instance, inhibition of NF-κB activation by a macrophage-restricted deletion of inhibitor of κB (IκB)kinase-2 (IKK-2) increases atherosclerosis in mice [24]
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