Targeting RUNX1 as a novel treatment modality for pulmonary arterial hypertension

Area of Science:

• Cardiovascular Research
• Hematology
• Cell Biology

Background:

• Pulmonary arterial hypertension (PAH) is a severe, incurable disease.
• RUNX1-dependent transformation of endothelial progenitor cells is implicated in PAH pathogenesis.
• The therapeutic efficacy of RUNX1 inhibition in established PAH is unknown.

Purpose of the Study:

• To determine if RUNX1 inhibition can reverse established Sugen/hypoxia (SuHx)-induced pulmonary hypertension (PH) in rats.
• To elucidate the underlying mechanisms of RUNX1 inhibition in PH.

Main Methods:

• Administration of a specific RUNX1 inhibitor (Ro5-3335) in a rat SuHx-PH model.
• Assessment of lung macrophage recruitment and activation in vitro and in vivo.
• Generation of conditional knockout mice (VE-cadherin-CreERT2; ZsGreen, Cdh5-CreERT2; Runx1(flox/flox), LysM-Cre; Runx1(flox/flox)) for lineage tracing and gene deletion studies.

Main Results:

• RUNX1 inhibition prevented, halted, and reversed established SuHx-induced PH in rats.
• RUNX1 inhibition significantly reduced lung macrophage recruitment and activation.
• Lineage tracing confirmed RUNX1-dependent endothelial to hematopoietic transformation in SuHx-PH.
• Tissue-specific deletion of Runx1 in adult endothelium or myeloid cells prevented SuHx-PH development.

Conclusions:

• RUNX1 inhibition effectively reverses established pulmonary hypertension.
• Blocking RUNX1-dependent endothelial to hematopoietic transformation and pulmonary macrophage activity may offer a novel therapeutic strategy for PAH.
• RUNX1 is essential for the development of pulmonary hypertension.