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BAS/BSCR YIA abstract
YIA4 C Jun N-terminal kinase promotes endothelial activation at atherosclerosis-susceptible sites by enhancing expression of NF-κB transcription factors
  1. Simon Cuhlmann1,2,
  2. Kim van der Heiden1,
  3. Mustafa Zakkar1,
  4. Hera Chaudhury1,
  5. Le Anh Luong1,
  6. Justin Mason1,
  7. Dorian O Haskard1,
  8. Harald Carlsen3,
  9. Robert Krams2,
  10. Paul C Evans1
  1. 1BHF Cardiovascular Sciences Unit, National Heart and Lung Institute, Imperial College London, UK
  2. 2Department of Bioengineering, Imperial College London, UK
  3. 3Department of Nutrition, University of Oslo, Norway


Atherosclerosis develops predominantly at branches and bends in arteries that are exposed to disturbed flow which exerts low, oscillatory shear stress on endothelial cells (ECs). We demonstrated that c-Jun N-terminal kinase (JNK) is activated in ECs at atherosusceptible but not atheroprotected sites. Transcriptome profiling of cultured ECs treated with a pharmacological inhibitor revealed that JNK functions as a positive regulator of NF-κB transcription factors, which promote inflammation by inducing inflammatory molecules (eg, VCAM-1). This observation was confirmed by silencing of JNK1 and ATF2 (a downstream transcription factor), which led to reduced NF-κB expression in cultured ECs. We validated our findings by demonstrating that EC expression of NF-κB and VCAM-1 and the accumulation of CD68-positive macrophages was elevated at atherosusceptible sites compared with atheroprotected sites in aortas of wild-type mice. Genetic deletion of JNK1 suppressed NF-κB and VCAM-1 expression, and reduced macrophage accumulation at the atherosusceptible site, indicating that JNK1 positively regulates NF-κB expression and inflammation. To establish a causal relationship between shear stress and JNK activity, we altered blood flow in the murine carotid artery by placing a constrictive cuff. We observed that low, oscillatory shear stress can enhance JNK activity, NF-κB and VCAM-1 expression in ECs and promote macrophage accumulation in arteries. We conclude that JNK1-ATF2 signalling promotes EC activation and inflammation at atheroprone sites exposed to low, oscillatory shear stress by enhancing NF-κB expression. Our findings illuminate a novel level of cross-talk between the NF-κB and JNK signalling pathways that may influence the spatial distribution of atherosclerotic lesions.

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  • Funding British Heart Foundation and NHLI Trustees Foundation.