What question did this study set out to answer?

This research aims to understand the role of SIX1 in endothelial dysfunction and pulmonary arterial hypertension.

February 6, 2026

Sine oculis homeobox 1 drives endothelial dysfunction in preclinical pulmonary arterial hypertension

Key Points

This research aims to understand the role of SIX1 in endothelial dysfunction and pulmonary arterial hypertension.
Examined SIX1 expression in human pulmonary arteries with pulmonary arterial hypertension.
Utilized siRNA to silence SIX1 in vitro and studied its effects on endothelial dysfunction.
Conducted endothelial-specific Six1 knockout in mice to assess pulmonary hemodynamics and right ventricular function.
Employed virtual screening and surface plasmon resonance to identify inhibitors of SIX1 transcriptional activity.
Performed multiomics profiling to identify targets of SIX1 in endothelial dysfunction.
SIX1 expression increased in the endothelia of pulmonary arteries from PAH and idiopathic pulmonary fibrosis patients.
Silencing SIX1 inhibited several markers of endothelial dysfunction in vitro.
Endothelial-specific Six1 knockout improved pulmonary hemodynamics and right ventricular function in mice.
Zafirlukast inhibited SIX1 transcriptional activity and ameliorated hypoxia-induced dysfunction.
MAST4 phosphorylated MAPK1/3, linking SIX1 to the mechanism of endothelial dysfunction.

Abstract

Endothelial dysfunction plays a critical role in the initiation and progression of vascular remodeling and pulmonary arterial hypertension (PAH). Sine oculis homeobox 1 ( SIX1 ) is a developmentally restricted transcription factor, and its expression ceases upon the completion of embryonic development. Deletion of Six1 impairs the differentiation of pulmonary vascular endothelial cells, resulting in pulmonary vascular defects and postnatal death. In this study, we found that SIX1 was increased in the endothelia of pulmonary arteries from patients with PAH and from patients with idiopathic pulmonary fibrosis–associated pulmonary hypertension (PH). Silencing SIX1 using siRNA inhibited hypoxia-induced endothelial dysfunction in vitro, including proliferation, endothelial-to-mesenchymal transition, and endothelin-1 release. Endothelial-specific Six1 knockout improved pulmonary hemodynamics, endothelial dysfunction, pulmonary artery remodeling, and right ventricular function in SU5416/hypoxia (SuHx)–induced PH mice. Moreover, endothelial-specific Six1 overexpression mediated by adeno-associated virus induced a spontaneous PH in wild-type C57BL/6 mice. Structure-based virtual screening and surface plasmon resonance analysis demonstrated that zafirlukast was an inhibitor of SIX1 transcriptional activity. Zafirlukast suppressed hypoxia-induced endothelial dysfunction in vitro and reversed SuHx-induced PH in Sprague-Dawley rats. Mechanistically, multiomics profiling of hypoxia-induced endothelial dysfunction in vitro revealed that microtubule-associated serine/threonine kinase family member 4 ( MAST4 ) was a target of SIX1. MAST4 phosphorylated the Thr 185/202 sites of mitogen-activated protein kinases 1 and 3 (MAPK1/3), resulting in endothelial dysfunction. Overall, we found that SIX1 was a driver for endothelial dysfunction and PH through regulating MAST4 transcription and subsequently MAPK1/3 activation. Targeting SIX1 may be a promising strategy for PAH treatment and drug development.

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Cite This Study

Liu et al. (Wed,) studied this question.

synapsesocial.com/papers/698585db8f7c464f2300985d https://doi.org/https://doi.org/10.1126/scitranslmed.adu6425

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