SIX1 mediates pulmonary arterial hypertension endothelial dysfunction through the IL-6/STAT3 axis

Area of Science:

• Cardiovascular Research
• Molecular Biology
• Pathophysiology

Background:

• Pulmonary arterial hypertension (PAH) is a severe cardiovascular disease characterized by elevated pulmonary artery pressure, right ventricular hypertrophy, endothelial dysfunction, and vascular remodeling.
• Inflammation plays a critical role in the progression of PAH.
• This study investigates the role and mechanism of sine oculis homeobox 1 (SIX1) in PAH pathogenesis.

Purpose of the Study:

• To elucidate the role of SIX1 in pulmonary arterial hypertension (PAH) using transcriptomics and integrated experimental models.
• To identify SIX1 as a potential therapeutic target for PAH.
• To explore the underlying molecular mechanisms involving SIX1 in PAH progression.

Main Methods:

• Transcriptomic analysis of mouse lung tissues using Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment and weighted gene co-expression network analysis (WGCNA).
• Prediction of binding sites between SIX1 and STAT3 using the JASPAR database.
• Validation using in vivo and in vitro PAH models, including hemodynamic and histopathological assessments, Western blot, RT-qPCR, immunofluorescence, and cellular assays (knockdown, viability, migration, proliferation, apoptosis).

Main Results:

• SIX1 expression positively correlated with clinical and pathological indices of PAH.
• SIX1 was significantly induced in vivo and in vitro, predominantly in endothelial cells.
• SIX1 knockdown reversed IL-6-induced endothelial cell proliferation and migration, accompanied by inhibition of STAT3 phosphorylation and SIX1-STAT3 colocalization.

Conclusions:

• SIX1 aggravates endothelial dysfunction in PAH via the IL-6/STAT3 signaling axis.
• SIX1 represents a promising therapeutic target for pulmonary arterial hypertension.
• Targeting the SIX1-STAT3 interaction could offer a novel treatment strategy for PAH.