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)-kappa B pathway is involved in arterial inflammation. Although the signaling pathways that regulate transcriptional activation of NF-kappa B are defined, the mechanisms that regulate the expression levels of NF-kappa B transcription factors are uncertain. Objective: We studied the signaling mechanisms that regulate RelA NF-kappa B 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-kappa B expression and macrophage accumulation at an atherosusceptible site. We hypothesized that JNK signaling to NF-kappa B 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-kappa B expression and inflammation in murine carotid arteries via JNK1. Conclusions: We demonstrate that disturbed blood flow promotes arterial inflammation by inducing NF-kappa B expression in endothelial cells via JNK-ATF2 signaling. Thus, our findings illuminate a novel form of JNK-NF-kappa B crosstalk that may determine the focal nature of arterial inflammation and atherosclerosis. (Circ Res. 2011;108:950-959.)