(964.4) Drp1-dependent Regulation of RelA/p65 Is Critical for Endothelial Cell Inflammation

Poster Board Number: E656

Mohammad Shadab (University of Rochester Medical Center), Rauf Najar (University of Rochester Medical Center), Fabeha Fazal (University of Rochester Medical Center), Arshad Rahman (University of Rochester Medical Center)

Endothelial cell (EC) inflammation is a major pathogenic feature of many diseases including acute lung injury (ALI). However, the role of the dynamin-related protein 1 (Drp1), a mitochondrial fission factor, in regulating EC inflammation is poorly understood. We show here that Drp1 is a critical mediator of EC inflammation via its ability to control NF-kB activation.  When Drp1 is disabled, expression of adhesion molecules (ICAM-1, VCAM-1) and cytokines/chemokines (IL-6, MCP-1) is markedly reduced in cells stimulated with thrombin.  Drp1-depleted cells were also impaired in their ability to activate NF-kB by thrombin. Mechanistic study revealed that thrombin-induced phosphorylation and nuclear DNA binding of RelAp65 was inhibited in Drp1-depleted cells. Surprisingly, the thrombin-induced degradation of IκBα in the cytosol remained unaffected in Drp1-depleted cells, suggesting a defect in the translocation of released RelA/p65 to the nucleus in these cells. Indeed, nuclear translocation of RelA/p65 caused by thrombin was inhibited in Drp1-depleted cells.  Together, these data uncover a novel function of Drp1 in mediating EC inflammation via regulation of phosphorylation and nuclear translocation of RelA/p65.

Supported by: NIH (GM130463, HL148695, HL130870).