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

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 (<i>n</i> = 241), SLE-nonPAH patients (<i>n</i> = 736), and healthy controls (<i>n</i> = 996) identified rare <i>TRAF5</i> 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, <i>p</i> = 0.029) and 1.13% in healthy controls (11/977, 95% CI, 1.414-8.427, <i>p</i> = 0.008). <i>TRAF5</i> expression was significantly reduced in SLE-PAH variant carriers compared with SLE-PAH non-carriers or SLE-nonPAH patients (<i>p</i> < 0.01). <i>TRAF5</i> 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 <i>TRAF5</i> expression and increased apoptosis in arterial endothelial cells (ECs), with BMP/TGF-β pathway activation. <i>In vitro</i> studies confirmed that <i>TRAF5</i> deficiency impaired the functions of pulmonary arterial ECs. Moreover, endothelium-specific <i>TRAF5</i> overexpression in an SLE-PAH mouse model attenuated pulmonary hypertension. These findings suggest that <i>TRAF5</i> loss-of-function exacerbates SLE-PAH by inducing EC dysfunction via the BMP/TGF-β signaling, suggesting potential therapeutic targets.