Abstract 9690: CIKS (Act1 Or TRAF3IP2) is Critical in High Glucose-induced Endothelial Dysfunction
Endothelial dysfunction is characterized by enhanced inflammatory cytokine and adhesion molecule expression, and endothelial-monocyte adhesion. The adapter molecule CIKS (connection to IKK and SAPK/JNK; also known as CIKS or TRAF3IP2) mediates NF-κB and AP-1 activation, and plays a role in inflammation and injury. Here we show that the high glucose (HG; 25 mM versus 5 mM D-glucose)-induced increase in endothelial-monocyte adhesion, and inhibition of human primary aortic endothelial cell (EC) migration and proliferation are reversed by CIKS knockdown. HG induced CIKS mRNA and protein expression via DPI-inhibitable Nox4-dependent ROS generation. Further, HG-enhanced CIKS promoter-dependent reporter gene activation was blocked by DPI, knockdown of Nox4, c-Jun or C/EBPβ or mutations in AP-1 or C/EBP binding sites. Interestingly, HG enhanced CIKS nuclear translocation. Coimmunoprecipitation and immunoblotting revealed CIKS/IKKβ/JNK physical association under basal conditions that was enhanced following HG treatment. Importantly, CIKS knockdown reversed HG-induced (i) IKKβ and JNK phosphorylation, (ii) p65 and c-Jun nuclear translocation, (iii) NF-κB- and AP-1-dependent proinflammatory cytokine (IL-18, IL-1β), chemokine (IL-8, MCP-1) and adhesion molecule (ICAM-1, VCAM-1) expression, (iv) endothelial-monocyte adhesion, and (v) inhibition in EC migration and proliferation. Similar to HG, AGE-BSA and ox-LDL markedly increased CIKS expression, CIKS/p65/c-Jun-dependent ICAM-1 and VCAM-1 expression, and endothelial-monocyte adhesion. Notably, aortas from type 1 diabetic animals (streptozotocin-induced, and autoimmune NOD or Akita) expressed high levels of CIKS, IL-18, and VCAM-1. These results indicate that HG enhances CIKS expression both in vitro and in vivo. Since CIKS mediates HG-induced NF-κB and AP-1-dependent inflammatory signaling and endothelial dysfunction, targeting CIKS may have broader protective effects in vascular diseases, including diabetes mellitus, dyslipidemia, and atherosclerosis.
- © 2012 by American Heart Association, Inc.