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Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in the lungs of mice with hypoxia-induced pulmonary hypertension. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.

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1819 Pulmonary hypertension is a progressive lung disease with poor prognosis due to the 20 consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction 21 are culprits for pathologically increased pulmonary arterial pressure, but their 22 underlying molecular mechanisms remain to be elucidated. Previous genome-wide 23 association studies revealed a significant correlation between the genetic locus of family 24 with sequence similarity 13, member A (FAM13A) and various lung diseases such as 25 chronic obstructive pulmonary disease and pulmonary fibrosis; however whether 26 FAM13A is also involved in the pathogenesis of pulmonary hypertension remained 27 unknown. Here, we identified a significant role of FAM13A in the development of 28 pulmonary hypertension. FAM13A expression was reduced in mouse lungs of 29 hypoxia-induced pulmonary hypertension model. We identified that FAM13A was 30 expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A 31 exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association 32 with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated 3 33 endothelial-to-mesenchymal transition potentially by inhibiting -catenin signaling in 34 pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in 35 the development of pulmonary hypertension, and therefore increasing and/or preserving 36 FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic 37 strategy for the treatment of pulmonary hypertension. 38 39 Introduction 40 41 Pulmonary hypertension is a progressive and fatal lung disease diagnosed by a 42 sustained elevation of pulmonary arterial pressure more than 20 mmHg [1]. Pulmonary 43 arterial hypertension including idiopathic pulmonary arterial hypertension and 44 pulmonary hypertension related with collagen disease is characterized by pathological 45 pulmonary artery remodeling such as intimal and medial thickening of muscular arteries, 46 vaso-occlusive lesions, and fully muscularized small diameter vessels that are normally 47 non-muscular peripheral vessels. These vascular remodeling is a result from endothelial 48 cell dysfunction, smooth muscle cell and endothelial cell proliferation, and also cellular 4 49 transdifferentiation [2]. Although detailed molecular mechanisms remain to be 50 elucidated, many pathogenic pathways in pulmonary arterial hypertension have been 51 revealed. These include TGF- signaling, inflammation, pericyte-mediated vascular 52 remodeling, iron homeostasis, and endothelial-to-mesenchymal transition (EndMT) [3]. 53 Recent genome-wide association studies identified family with sequence similarity 54 13, member A (FAM13A) gene as a genetic locus associated with pulmonary function 55 [4], and it is known to be associated with lung diseases including chronic obstructive 56 pulmonary disease (COPD) [5], asthma [6] and pulmonary fibrosis [7-9]. Moreover, 57 causative role of FAM13A in the development of COPD...