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

• Published in: The FASEB journal Vol. 36 Suppl 1
• Main Authors: Shadab, Mohammad, Najar, Rauf A, Fazal, Fabeha, Rahman, Arshad
• Format: Journal Article
• Language: English
• Published: United States 01.05.2022
• ISSN: 1530-6860
• DOI: 10.1096/fasebj.2022.36.S1.L7602

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-κB 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-κB 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.