Author:

Keywords:

arterial inflammation, blood flow, c-Jun N-terminal kinase, NF-kappa B, Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Hematology, Peripheral Vascular Disease, Cardiovascular System & Cardiology, CELL-ADHESION MOLECULE-1, NECROSIS-FACTOR-ALPHA, ATHEROSCLEROTIC PLAQUE INFLAMMATION, POSITRON-EMISSION-TOMOGRAPHY, ENDOTHELIAL SHEAR-STRESS, HUMAN CORONARY-ARTERIES, NEOINTIMAL FORMATION, OXIDATIVE STRESS, LESION FORMATION, GENE-EXPRESSION, Animals, Aorta, Cells, Cultured, Endothelium, Vascular, Gene Expression Regulation, Enzymologic, Humans, Inflammation Mediators, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitogen-Activated Protein Kinase 8, Regional Blood Flow, Shear Strength, Transcription Factor RelA, Up-Regulation, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, Cardiovascular System & Hematology, 3201 Cardiovascular medicine and haematology, 3202 Clinical sciences

Abstract:

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.