Presentation Information
[III-TLR-1]Pathological mechanisms of Down syndrome-associate pulmonary hypertension
○Kazutoshi Ueda, Hidehiro Suginobe, Kazuhisa Hashimoto, Chika Yoshihara, Atsuko Ueyama, Ryo Ishii, Jun Narita, Yasuji Kitabatake, Hidekazu Ishida (Department of Pediatrics, The University of Osaka Graduate School of Medicine)
Keywords:
Down syndrome,pulmonary hypertension,DYRK1A
Background: Down syndrome (DS) is associated with an increased incidence of pulmonary hypertension (PH). Factors that contribute to the progression of PH in DS include problems with the pulmonary vascular endothelial cells (ECs), although the molecular mechanisms remain unknown. We investigated the molecular pathological mechanisms of PH in DS with the aim of developing a new therapy.Methods: We employed the isogenic pairs of T21-induced pluripotent stem cells (iPSCs) derived ECs and genetically corrected disomy 21 (cDi21)-iPSCs derived ECs, and the Ts1Cje mice, DS model mice. Sugen/hypoxia was exposed to induce PH.Results: In T21-ECs, apoptosis and mitochondrial reactive oxygen species were increased, and angiogenesis and oxygen consumption rate were impaired compared with cDi21-ECs. The RNA-sequencing identified that EGR1 on chromosome 5 was upregulated in T21-ECs. We revealed that DYRK1A on chromosome 21 was responsible to increase EGR1 expression via PPARG suppression by using DYRK1A inhibitor and PPARG agonist, pioglitazone.Right ventricular systolic pressure (RVSP) was significantly higher in Ts1Cje mice than wild-type littermates after sugen/hypoxia exposure. Pulmonary vascular medial thickness was increased in Ts1Cje mice, and immunostaining revealed stronger signals for EGR1, caspase-3, and weaker for PPARG. Pioglitazone ameliorated RVSP and vascular remodeling in Ts1Cje mice and suppressed EGR1 expression.Conclusion: DYRK1A/PPARG/EGR1 pathway plays a central role in the pathogenesis of PH in DS. Pioglitazone may represent a promising therapy for DS-associated PH.