CTRP7 as a molecular biomarker for predicting responsiveness to pulmonary vasodilators: insights from human and animal studies in pulmonary arterial hypertension

Background Pulmonary arterial hypertension (PAH) is a life-threatening condition. While pulmonary vasodilators help manage PAH, their impact on prognosis remains limited, partly due to the lack of biomarkers to guide therapy selection. This study aimed to identify molecular predictors of responsiveness to pulmonary vasodilators through clinical and preclinical investigations. Methods and Results RNA sequencing of pulmonary artery smooth muscle cells (PASMCs) from patients with and without PAH identified 3,017 differentially expressed genes, including reduced expression of the PGI2 receptor (PTGIR). Further analysis of PASMCs with varying PTGIR expressions identified an additional 704 genes. Plasma samples were then examined to identify potential biomarers (Fig. A). Both RNA sequencing analyses revealed a significant increase in CTRP7 mRNA in PASMCs from PAH patients (log2 fold change 5.37), particularly in cells with reduced PTGIR expression (log2 fold change 2.18). Plasma analysis confirmed higher CTRP7 levels in PAH patients compared to non-PH individuals (PAH, n = 114 vs. non-PH, n = 70; 19.68 [9.8–90.5] vs. 11.8 [0.58–61.57], p < 0.01) (Fig. B). Single-cell and plasma analyses showed a significant correlation between CTRP7 and IL-6 levels (p < 0.001) (Fig. C, D). Mechanistically, IL-6 upregulated CTRP7 expression in PASMCs, as demonstrated by chromatin immunoprecipitation and western blotting (Fig. E). CTRP7 reduced PTGIR expression via Rab5a-mediated internalization (Fig. F, G), leading to diminished responsiveness to selexipag (a PGI2 analogue). Consistent with these findings, hypoxic PH mice exhibited reduced PTGIR expression in pulmonary arteries, correlating with poor response to selexipag (low cardiac output and persistent pulmonary vascular resistance). This effect was reversed by IL-6 receptor blockade or AAV-mediated CTRP7 silencing (Fig. H). Finally, PAH patients were stratified based on median plasma CTRP7 levels (19.68 ng/mL). Those with higher CTRP7 levels showed a weaker response to PGI2 analogs compared to those with lower levels (Higher CTRP7 [n = 40] vs. Lower CTRP7 [n = 38]; -115 ± 167.6 vs. -209.0 ± 188.4 dyne-sec-cm⁻⁵, p < 0.01) (Fig. I). Conclusions CTRP7 was identified as a potential biomarker for predicting responsiveness to PGI2 analogs in PAH. PAH patients had higher plasma CTRP7 levels than non-PH individuals, and CTRP7 regulated PTGIR internalization through the IL-6-Rab5a axis, influencing the efficacy of selexipag. These findings suggest that CTRP7 may play a crucial role in guiding PAH treatment strategies.