Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation.
RATIONALE: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. OBJECTIVE: We studied th...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2011
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| _version_ | 1797071242713366528 |
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| author | Cuhlmann, S Van der Heiden, K Saliba, D Tremoleda, J Khalil, M Zakkar, M Chaudhury, H Luong, L Mason, J Udalova, I Gsell, W Jones, H Haskard, DO Krams, R Evans, P |
| author_facet | Cuhlmann, S Van der Heiden, K Saliba, D Tremoleda, J Khalil, M Zakkar, M Chaudhury, H Luong, L Mason, J Udalova, I Gsell, W Jones, H Haskard, DO Krams, R Evans, P |
| author_sort | Cuhlmann, S |
| collection | OXFORD |
| description | RATIONALE: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. OBJECTIVE: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. METHODS AND RESULTS: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. CONCLUSIONS: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. |
| first_indexed | 2024-03-06T22:50:27Z |
| format | Journal article |
| id | oxford-uuid:5e9bb281-8759-4269-91e6-9587d61633d4 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T22:50:27Z |
| publishDate | 2011 |
| record_format | dspace |
| spelling | oxford-uuid:5e9bb281-8759-4269-91e6-9587d61633d42022-03-26T17:41:46ZDisturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:5e9bb281-8759-4269-91e6-9587d61633d4EnglishSymplectic Elements at Oxford2011Cuhlmann, SVan der Heiden, KSaliba, DTremoleda, JKhalil, MZakkar, MChaudhury, HLuong, LMason, JUdalova, IGsell, WJones, HHaskard, DOKrams, REvans, PRATIONALE: The nuclear factor (NF)-κB pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-κB are defined, the mechanisms that regulate the expression levels of NF-κB transcription factors are uncertain. OBJECTIVE: We studied the signaling mechanisms that regulate RelA NF-κB subunit expression in endothelial cells (ECs) and their role in arterial inflammation. METHODS AND RESULTS: Gene silencing and chromatin immunoprecipitation revealed that RelA expression was positively regulated by c-Jun N-terminal kinase (JNK) and the downstream transcription factor ATF2 in ECs. We concluded that this pathway promotes focal arterial inflammation as genetic deletion of JNK1 reduced NF-κB expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-κB may be controlled by mechanical forces because atherosusceptibility is associated with exposure to disturbed blood flow. This was assessed by positron emission tomography imaging of carotid arteries modified with a constrictive cuff, a method that was developed to study the effects of disturbed flow on vascular physiology in vivo. This approach coupled to en face staining revealed that disturbed flow elevates NF-κB expression and inflammation in murine carotid arteries via JNK1. CONCLUSIONS: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-κB expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-κB crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. |
| spellingShingle | Cuhlmann, S Van der Heiden, K Saliba, D Tremoleda, J Khalil, M Zakkar, M Chaudhury, H Luong, L Mason, J Udalova, I Gsell, W Jones, H Haskard, DO Krams, R Evans, P Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title | Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title_full | Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title_fullStr | Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title_full_unstemmed | Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title_short | Disturbed blood flow induces RelA expression via c-Jun N-terminal kinase 1: a novel mode of NF-κB regulation that promotes arterial inflammation. |
| title_sort | disturbed blood flow induces rela expression via c jun n terminal kinase 1 a novel mode of nf κb regulation that promotes arterial inflammation |
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