TNF-α signaling regulates RUNX1 function in endothelial cells.

Abstract

Runt-related transcription factor 1 (RUNX1) acts as a mediator of aberrant retinal angiogenesis and has been implicated in the progression of proliferative diabetic retinopathy (PDR). Patients with PDR, retinopathy of prematurity (ROP), and wet age-related macular degeneration (wet AMD) have been found to have elevated levels of Tumor Necrosis Factor-alpha (TNF-α) in the eye. In fibrovascular membranes (FVMs) taken from patients with PDR RUNX1 expression was increased in the vasculature, while in human retinal microvascular endothelial cells (HRMECs), TNF-α stimulation causes increased RUNX1 expression, which can be modulated by RUNX1 inhibitors. Using TNF-α pathway inhibitors, we determined that in HRMECs, TNF-α-induced RUNX1 expression occurs via JNK activation, while NF-κB and p38/MAPK inhibition did not affect RUNX1 expression. JNK inhibitors were also effective at stopping high D-glucose-stimulated RUNX1 expression. We further linked JNK to RUNX1 through Activator Protein 1 (AP-1) and investigated the JNK-AP-1-RUNX1 regulatory feedback loop, which can be modulated by VEGF. Additionally, stimulation with TNF-α and D-glucose had an additive effect on RUNX1 expression, which was downregulated by VEGF modulation. These data suggest that the downregulation of RUNX1 in conjunction with anti-VEGF agents may be important in future treatments for the management of diseases of pathologic ocular angiogenesis.

• Authors: Hannah A B Whitmore, Dhanesh Amarnani, Michael O'Hare, Santiago Delgado-Tirado, Lucia Gonzalez-Buendia, Miranda An, Julien Pedron, John H Bushweller, Joseph F Arboleda-Velasquez, Leo A Kim
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 35 Issue 2 Pg. e21155 (02 2021) ISSN: 1530-6860 [Electronic] United States
• PMID: 33135824 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• RUNX1 protein, human
• Runx1 protein, mouse
• TNF protein, human
• Tumor Necrosis Factor-alpha
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Glucose

Topics

• Animals
• Cells, Cultured
• Choroidal Neovascularization (metabolism)
• Core Binding Factor Alpha 2 Subunit (antagonists & inhibitors, metabolism)
• Diabetic Retinopathy (metabolism)
• Disease Models, Animal
• Endothelial Cells (drug effects, metabolism)
• Glucose (pharmacology)
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mice, Inbred C57BL
• Retina (cytology, metabolism)
• Retinopathy of Prematurity (metabolism)
• Tumor Necrosis Factor-alpha (antagonists & inhibitors, metabolism, pharmacology)
• Up-Regulation (drug effects)
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)
• Wet Macular Degeneration (metabolism)