Abstract
Bone morphogenic protein receptor 2 (BMPR2) expression and signaling are impaired in pulmonary arterial hypertension (PAH). How BMPR2 signaling is decreased in PAH is poorly understood. Protein tyrosine phosphatases (PTPs) play important roles in vascular remodeling in PAH. To identify whether PTPs modify BMPR2 signaling, we used a siRNA-mediated high-throughput screening of 22,124 murine genes in mouse myoblastoma reporter cells using ID1 expression as readout for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in healthy human pulmonary arterial endothelial cells (PAECs) either silenced by siRNA or exposed to hypoxia and confirmed its relevance to PAH by measuring PTPN1 levels in blood and PAECs collected from PAH patients. We identified PTPN1 as a novel regulator of BMPR2 signaling in PAECs, which is downregulated in the blood of PAH patients, and documented that downregulation of PTPN1 is linked to endothelial dysfunction in PAECs. These findings point to a potential involvement for PTPN1 in PAH and will aid in our understanding of the molecular mechanisms involved in the disease.
Funder
National Institutes of Health
Stanford Vera Moulton Wall Center for Pulmonary Vascular Diseases
U.S. Department of Defense
Reference37 articles.
1. Promising therapeutic approaches in pulmonary arterial hypertension;Ali;Curr. Opin. Pharmacol.,2021
2. Dannewitz Prosseda, S., Ali, M.K., and Spiekerkoetter, E. (2020). Novel Advances in Modifying BMPR2 Signaling in PAH. Genes, 12.
3. Genetic ablation of the BMPR2 gene in pulmonary endothelium is sufficient to predispose to pulmonary arterial hypertension;Hong;Circulation,2008
4. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle;West;Circ. Res.,2004
5. Mice expressing BMPR2R899X transgene in smooth muscle develop pulmonary vascular lesions;West;Am. J. Physiol. Lung Cell. Mol. Physiol.,2008
Cited by
1 articles.
订阅此论文施引文献
订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献