TNF-α signaling regulates RUNX1 function in endothelial cells

Area of Science:

• Ophthalmology
• Molecular Biology
• Cell Biology

Background:

• Aberrant retinal angiogenesis contributes to vision-threatening diseases like proliferative diabetic retinopathy (PDR).
• Elevated Tumor Necrosis Factor-alpha (TNF-α) is observed in PDR, retinopathy of prematurity (ROP), and wet age-related macular degeneration (wet AMD).
• Runt-related transcription factor 1 (RUNX1) is implicated in PDR progression and its expression is increased in fibrovascular membranes.

Purpose of the Study:

• To investigate the role of RUNX1 in TNF-α-induced and high D-glucose-stimulated retinal angiogenesis.
• To elucidate the signaling pathways regulating RUNX1 expression in human retinal microvascular endothelial cells (HRMECs).
• To explore the potential of targeting RUNX1 and its regulatory pathways, in combination with anti-VEGF agents, for treating pathologic ocular angiogenesis.

Main Methods:

• Stimulation of HRMECs with TNF-α and high D-glucose.
• Inhibition of TNF-α signaling pathways (JNK, NF-κB, p38/MAPK) and RUNX1.
• Investigation of the JNK-AP-1-RUNX1 regulatory feedback loop and modulation by VEGF.

Main Results:

• TNF-α stimulation increased RUNX1 expression in HRMECs via JNK activation, not NF-κB or p38/MAPK.
• JNK inhibitors suppressed both TNF-α- and high D-glucose-induced RUNX1 expression.
• A JNK-AP-1-RUNX1 regulatory feedback loop, modulated by VEGF, was identified.
• Combined TNF-α and D-glucose stimulation had an additive effect on RUNX1 expression, which was reduced by VEGF modulation.

Conclusions:

• RUNX1 expression in retinal angiogenesis is regulated by the JNK-AP-1 pathway, influenced by TNF-α, high glucose, and VEGF.
• Targeting RUNX1, particularly via JNK inhibition, alongside anti-VEGF therapies, presents a potential therapeutic strategy for pathologic ocular angiogenesis.