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bioRxiv · 10.1101/2022.11.27.518092

PTPN1 deficiency modulates BMPR2 signaling and induces endothelial dysfunction in Pulmonary Arterial Hypertension

Ali, M. K.·Tian, X.·Zhao, L.·Schimmel, K.·Rhodes, C. J.·Wilkins, M.·Nicolls, M. R.·Spiekerkoetter, E.
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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 read-out for BMPR2 signaling. We further experimentally validated the top hit, PTPN1 (PTP1B), in human healthy 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.

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Ali, M. K., Tian, X., Zhao, L., Schimmel, K., Rhodes, C. J., Wilkins, M., Nicolls, M. R., Spiekerkoetter, E.. 2022-11-28. PTPN1 deficiency modulates BMPR2 signaling and induces endothelial dysfunction in Pulmonary Arterial Hypertension. https://doi.org/10.1101/2022.11.27.518092

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