Abstract 4354856: Pathological mechanisms of Down syndrome-associate pulmonary arterial hypertension

Background: Down syndrome (DS) is the most prevalent chromosomal disorder, caused by trisomy of human chromosome 21. DS is associated with an increased incidence of pulmonary arterial hypertension (PAH). We previously reported that the DYRK1A/PPARG/EGR1 signaling pathway, which induces pulmonary vascular endothelial dysfunction, plays a central role in DS-associated PAH, using patient-derived induced pluripotent stem cells (iPSCs) and lung tissue. In this study, we investigated the molecular pathological mechanisms of PAH in DS using an animal model, with the aim of developing a therapeutic approach targeting the EGR1 pathway. Methods: The Ts1Cje mouse, a well-established DS model carrying a segmental trisomy of mouse chromosome 16 including DYRK1A, was used. To induce PAH, a “second hit” such as environmental stress or genetic predisposition is required. We exposed Ts1Cje mice to chronic hypoxia for three weeks, followed by one week of normoxia after SU5416 injection. We assessed hemodynamics and pulmonary artery histology using Elastica van Gieson staining and immunohistochemistry for EGR1, PPARG, Ki67, caspase-3, and α-smooth muscle actin (SMA) Results: Right ventricular systolic pressure was significantly higher in Ts1Cje mice than in wild-type littermates, indicating more severe PAH. Pulmonary vascular medial thickness was increased in Ts1Cje mice, and immunostaining revealed stronger signals for EGR1, caspase-3, and α-SMA, and weaker signals for PPARG compared to wild-type controls. These findings were consistent with those obtained from DS patient-derived iPSCs. Quantitative PCR analysis of pulmonary arteries collected by laser microdissection showed elevated EGR1 expression in Ts1Cje mice relative to wild-type littermates. For therapeutic evaluation, we administered pioglitazone, a modulator of the PPARG/EGR1 pathway, to Ts1Cje mice for two weeks, alongside a placebo group. Hemodynamic and histological assessments demonstrated that pioglitazone ameliorated PAH and vascular remodeling in Ts1Cje mice and suppressed EGR1 expression. Conclusion: Our findings confirm that the DYRK1A/PPARG/EGR1 pathway plays a central role in the pathogenesis of PAH in a DS mouse model. Pioglitazone may represent a promising therapeutic agent for DS-associated PAH.