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

BACKGROUND AND

OBJECTIVE

Pulmonary arterial hypertension (PAH) is characterized by progressive pulmonary vascular remodeling, which is driven in part by endothelial dysfunction. Growth differentiation factor 11 (GDF11) has emerged as an important regulator of vascular homeostasis; however, its role in pulmonary artery endothelial cell (PAEC) pyroptosis remains unclear. This study aimed to define the contribution of GDF11 to hypoxia-induced PAH and its mechanistic association with inflammasome activation.

METHODS

Endothelial-specific Gdf11 knockout mice were exposed to chronic hypoxia to evaluate hemodynamics, right ventricular hypertrophy, pulmonary vascular remodeling, and endothelial pyroptosis. In vitro, PAECs were subjected to GDF11 knockdown or adenoviral-mediated overexpression. Pyroptosis and downstream signaling were assessed by Western blotting, Annexin V/propidium iodide staining, lactate dehydrogenase release assay, Hoechst/propidium iodide imaging, immunofluorescence, and chromatin immunoprecipitation.

RESULTS

GDF11 expression was increased in hypoxic lung tissues and PAECs. Endothelial-specific deletion of Gdf11 significantly reduced right ventricular systolic pressure, right ventricular hypertrophy, and pulmonary vascular remodeling, and suppressed hypoxia-induced PAEC pyroptosis. In vitro, GDF11 knockdown attenuated hypoxia-induced pyroptosis, whereas GDF11 overexpression exacerbated this response. Mechanistically, SOX2 was identified as a downstream transcriptional effector of GDF11 and was found to directly bind to the Nlrp3 promoter, thereby promoting inflammasome activation and pyroptosis.

CONCLUSION

These findings identify a previously unrecognized GDF11-SOX2-NLRP3 axis that promotes pulmonary endothelial pyroptosis and accelerates PAH progression. Targeting this pathway may provide new opportunities for biomarker development and therapeutic intervention in PAH.