GDF11 regulates hypoxia-induced pulmonary endothelial cell pyroptosis through SOX2/NLRP3 axis

Area of Science:

• Vascular Biology
• Cellular Signaling
• Pulmonary Hypertension Research

Background:

• Pulmonary arterial hypertension (PAH) involves pulmonary vascular remodeling and endothelial dysfunction.
• The role of Growth Differentiation Factor 11 (GDF11) in pulmonary artery endothelial cell (PAEC) pyroptosis is not well understood.
• Investigating GDF11's contribution to hypoxia-induced PAH and inflammasome activation is crucial.

Purpose of the Study:

• To define the role of GDF11 in hypoxia-induced pulmonary arterial hypertension (PAH).
• To elucidate the mechanistic link between GDF11, endothelial pyroptosis, and inflammasome activation in PAECs.
• To identify potential therapeutic targets within the GDF11 signaling pathway.

Main Methods:

• Utilized endothelial-specific Gdf11 knockout mice exposed to chronic hypoxia to assess PAH hallmarks.
• Employed in vitro studies with PAECs involving GDF11 knockdown and overexpression.
• Assessed pyroptosis and downstream signaling via Western blotting, flow cytometry, LDH assay, and molecular binding analyses.

Main Results:

• GDF11 expression increased in hypoxic conditions.
• Gdf11 deletion attenuated hypoxia-induced PAH, reducing vascular remodeling and PAEC pyroptosis.
• GDF11 directly regulates SOX2, which binds the NLRP3 promoter, driving inflammasome activation and pyroptosis.

Conclusions:

• Identified a novel GDF11-SOX2-NLRP3 signaling axis promoting pulmonary endothelial pyroptosis in PAH.
• This pathway significantly contributes to PAH progression.
• The GDF11-SOX2-NLRP3 axis represents a promising target for novel PAH biomarkers and therapeutics.