Proc Natl Acad Sci U S A. 2026 Jun 23;123(25):e2513158123. doi: 10.1073/pnas.2513158123. Epub 2026 Jun 15.
ABSTRACT
Schistosomiasis-associated pulmonary hypertension (Sch-PH) is the most common form of group I PH worldwide. Recently, data revealed that the preclinical Sch-PH animal model exhibited gut and lung microbiome dysbiosis, associated with significant lung endothelial cell (EC) dysfunction and microvascular apoptosis. However, the role of pro-/antiapoptosis sensors, such as the inhibitor of apoptosis protein 2 (c-IAP2) and the purinergic receptor P2X7 (P2X7R), remained unclear. Using Cdh5cre-ERT2;cIAP1-/-;cIAP2fl/fl animal model, this study investigated the contribution of endothelial c-IAP2 in this process, revealing pulmonary P2X7R overexpression as a putative target in the onset of Sch-PH. Pharmacologically, inhibition of P2X7R function confirmed its role in promoting lung EC death and disease progression. Moreover, data suggest that microbiome-associated metabolic alterations in Sch-PH seem linked to microvascular EC apoptosis driven by ATP/P2X7R overactivation and suppressed c-IAP2 expression. Indeed, genetic ablation of endothelial c-IAP2 expression was sufficient to induce PH-like features in mice, with echocardiography indicating a higher pulmonary acceleration time (PAT), PAT/pulmonary ejection time, and right ventricular free wall thickness (RVFWTH) after IP/IV-Egg challenge compared to controls, an effect linked to the female prevalence of the disease. These findings suggest a significant contribution of lung EC-P2X7R activation and c-IAP2 suppression to sex-linked Sch-PH pathology, highlighting them as promising therapeutic targets for this life-threatening illness.
PMID:42296370 | DOI:10.1073/pnas.2513158123