CTRP7 as a molecular biomarker associating with responsiveness to pulmonary vasodilators: insights from human and animal studies in pulmonary arterial hypertension.

Abstract

Aims: Pulmonary arterial hypertension (PAH) is a life-threatening condition. Although pulmonary vasodilators have shown promise in managing PAH, the improvement in prognosis is modest, partly because of a lack of biomarkers to guide their selection. Herein, we aimed to identify molecular-based predictors of responsiveness to pulmonary vasodilators using clinical and preclinical investigations.

Methods and results: RNA sequencing was conducted on cultured pulmonary artery smooth muscle cells (PASMCs) from patients with and without pulmonary hypertension (PH), identifying variations in 3017 genes. Next, we performed a case-control study (PAH, n = 114; non-PH, n = 70) and examined plasma samples to identify potential clinical biomarkers. PASMCs exhibited elevated expression of C1q/TNF-related protein 7 (CTRP7; log2 fold change 5.37, P < 0.01). Patients with PAH had higher plasma CTRP7 levels [19.7 (9.8-90.5)] than those without PH [11.8 (0.6-61.6) ng/mL; P < 0.01]. Plasma and single-cell assessments revealed a significant correlation between CTRP7 and interleukin (IL)-6 levels (P < 0.001). Chromatin immunoprecipitation demonstrated that IL-6 up-regulated CTRP7 in PASMCs. CTRP7 reduced the expression of prostacyclin analogue receptor (PTGIR) through Rab5a-mediated internalization, resulting in diminished responsiveness to selexipag (prostacyclin analogue). Consistent with human study results, PTGIR expression was reduced in the pulmonary arteries of hypoxic PH mice, correlating with limited responses to selexipag treatment (low cardiac output and persistent pulmonary artery resistance); this effect was mitigated by the IL-6-R neutralizing antibody or adeno-associated virus-mediated silencing of CTRP7 expression in the pulmonary arteries.

Conclusion: In patients with PAH, RNA sequencing of PASMCs revealed elevated expression of CTRP7 among candidate biomarkers. Patients with PAH had higher plasma CTRP7 levels than those without PH. Mechanistically, CTRP7 regulated PTGIR internalization via the IL-6-Rab5a axis, influencing responsiveness to selexipag. Herein, CTRP7 emerged as a crucial biomarker associating with responsiveness to prostacyclin analogues, advancing the development of PAH treatment strategies.