Abstract 12562: DYRK1A/PPARG/EGR1 Pathway Elicits Endothelial Dysfunctions and Predispose to Developing Pulmonary Hypertension in Down Syndrome

Introduction: Patients with Down syndrome (DS) have a higher prevalence of pulmonary arterial hypertension (PAH). Pulmonary vascular endothelial dysfunction has been recognized to be one of the predisposing factors to develop PAH, but pathophysiology of pulmonary endothelial cells in DS specific PAH is still unknown. Hypothesis: Endothelial dysfunctions contribute to developing PAH in DS. Methods: Induced pluripotent stem cell-derived vascular endothelial cells (iPSC-ECs) from DS patients were utilized for analyzing cellular and mitochondrial functions. A Cre-loxP mediated isogenic correction line of disomy 21 was established and used as a control. Results: DS-iPSC-ECs showed increased apoptosis, reduced angiogenesis, increased mitochondrial reactive oxygen species, and decreased ATP production, which were all consistent with features of endothelial dysfunctions previously reported in other types of PAH. RNA-seq revealed increased expression of EGR1 in DS-iPSC-ECs, and its inhibition restored cellular and mitochondrial dysfunctions, demonstrated by si EGR1 and pioglitazone treatment. Moreover, we revealed that increased expression of DYRK1a , one of the major pathogenic genes in DS critical region on chromosome 21, led to elevated EGR1 expression thorough PPARG suppression. These experimental results were reinforced by the observations that pulmonary ECs of a DS patient with severe PAH also exhibited increased EGR1. Conclusions: DYRK1A/PPARG/EGR1 pathway in DS is responsible for endothelial dysfunctions and might be a new therapeutic target for DS specific PAH.