Experimental pulmonary arterial hypertension in mice with a pathogenic SOX17 variant.

The SRY-box transcription factor 17 gene (SOX17) has been identified as a causative gene for pulmonary arterial hypertension (PAH), but its underlying mechanisms remain unclear. We conducted experiments using mice carrying the Sox17 variant confirmed in patients with PAH. Mice with the heterozygous Sox17 c.397 C > G (p.Pro133Ala) variant (Sox17+/Pro133Ala mice), identified in severe PAH patients resistant to combination therapy with pulmonary vasodilators, were created and raised in a hypoxic environment. The Fulton index, right ventricular systolic pressure, and medial wall thickness were increased in Sox17+/Pro133Ala mice compared with those in wild-type controls, suggesting the presence of PAH in Sox17+/Pro133Ala mice. RNA sequencing of murine lungs demonstrated that Cyp1b1 expression was elevated in the Sox17+/Pro133Ala mice. CYP1B1 encodes cytochrome P450 1B1, an enzyme that plays a key role in the metabolism of various endogenous and exogenous compounds, particularly in the oxidative metabolism of steroid hormones such as estrogens. CH-223,191, an aryl hydrocarbon receptor antagonist, suppressed Cyp1b1 expression, alleviating the PAH phenotype. Furthermore, the expressions of Bmpr2, Col4a1, and Col4a2, which were downregulated in Sox17+/Pro133Ala mice, were restored. These findings suggest that multiple pathways, including Cyp1b1, Bmpr2, and Col4a1/Col4a2, are interconnected and altered by a single base substitution in Sox17, and that PAH patients with SOX17 variants may develop PAH through these pathways. These results demonstrate that Sox17+/p.Pro133Ala mice exhibited right heart overload and pulmonary vascular remodeling when subjected to hypoxic stress, confirming that this mouse model mimics the human PAH phenotype.