Oxidative stress-responsive transcription factor ATF3 potentially mediates diabetic angiopathy

Area of Science:

• Endothelial cell biology
• Molecular mechanisms of angiogenesis
• Diabetic complications

Background:

• Previous studies identified ATF3 (activating transcription factor 3) as a gene correlating with in vitro tubulogenesis in NP31 endothelial cells.
• ATF3 is known to be responsive to cellular stress, including reactive oxygen species (ROS).

Purpose of the Study:

• To investigate the role of ATF3 in endothelial cell tubulogenesis and its potential involvement in diabetic angiopathy.
• To identify downstream targets of ATF3 in the context of angiogenesis.

Main Methods:

• cDNA microarray analysis to identify correlating genes.
• Small interfering RNA (siRNA) to inhibit ATF3 expression.
• Tetracycline-inducible system to control ATF3 expression in NP31 cells.
• Analysis of gene expression in H2O2-stimulated cells and diabetic rat models.

Main Results:

• Inhibition of ATF3 suppressed tube formation in NP31 cells expressing activated VEGFR-1.
• ATF3 induction in NP31 cells promoted tubulogenic ability.
• ATF3 regulated the expression of genes including CDK2, CDK4, p8, PAI-1, integrin alpha1, and MMP13, but not VEGF or VEGFR.
• Co-enhanced expression of ATF3, PAI-1, and p8 was observed in H2O2-stimulated cells and diabetic rat endothelial cells.

Conclusions:

• ATF3 is a key regulator of endothelial cell tubulogenesis.
• The ATF3 pathway, involving PAI-1 and p8, may contribute to pathological angiogenesis in ROS-associated diabetic complications.