Rare TRAF5 coding variants in systemic lupus erythematosus patients aggravate pulmonary hypertension via endothelial dysfunction

Public summary

* 3.78% of systemic lupus erythematosus-pulmonary arterial hypertension (PAH) patients have TRAF5 variants.

* TRAF5 knockout mice showed severe PAH; single-cell and in vitro studies revealed endothelial dysfunction.

* Endothelium-specific TRAF5 overexpression attenuates PAH in model mice, suggesting a therapeutic target.

Abstract

Pulmonary arterial hypertension (PAH) is a severe complication of systemic lupus erythematosus (SLE), associated with right heart failure and high mortality. This study investigates SLE-PAH pathogenesis using the CSTAR cohort and whole-exome sequencing. Gene-based burden analysis of SLE-PAH patients (n = 241), SLE-nonPAH patients (n = 736), and healthy controls (n = 996) identified rare TRAF5 coding variants in 3.78% of SLE-PAH cases (9/238) compared with 1.37% in SLE-nonPAH (10/728; 95% CI, 1.133–8.030, p = 0.029) and 1.13% in healthy controls (11/977, 95% CI, 1.414–8.427, p = 0.008). TRAF5 expression was significantly reduced in SLE-PAH variant carriers compared with SLE-PAH non-carriers or SLE-nonPAH patients (p < 0.01). TRAF5 knockout mice exhibited more severe pulmonary hypertension, right ventricular hypertrophy, and increased early mortality compared with wild-type mice. Single-cell RNA sequencing of lung tissue from knockout mice revealed reduced TRAF5 expression and increased apoptosis in arterial endothelial cells (ECs), with BMP/TGF-β pathway activation. In vitro studies confirmed that TRAF5 deficiency impaired the functions of pulmonary arterial ECs. Moreover, endothelium-specific TRAF5 overexpression in an SLE-PAH mouse model attenuated pulmonary hypertension. These findings suggest that TRAF5 loss-of-function exacerbates SLE-PAH by inducing EC dysfunction via the BMP/TGF-β signaling, suggesting potential therapeutic targets.