PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension

Md Khadem Ali; Xuefei Tian; Lan Zhao; Katharina Schimmel; Christopher J Rhodes; Martin R Wilkins; Mark R Nicolls; Edda F Spiekerkoetter

doi:10.3390/cells12020316

PTPN1 Deficiency Modulates BMPR2 Signaling and Induces Endothelial Dysfunction in Pulmonary Arterial Hypertension

Cells. 2023 Jan 14;12(2):316. doi: 10.3390/cells12020316.

Authors

Md Khadem Ali^{1

2}, Xuefei Tian^{1

2}, Lan Zhao^{1

2}, Katharina Schimmel^{1

2

3}, Christopher J Rhodes⁴, Martin R Wilkins⁴, Mark R Nicolls^{1

2}, Edda F Spiekerkoetter^{1

2}

Affiliations

¹ Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Stanford University, Stanford, CA 94305, USA.
² Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University, Stanford, CA 94305, USA.
³ Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁴ National Heart and Lung Institute, Hammersmith Campus, Imperial College London, London W12 0NN, UK.

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.

Keywords: BMPR2 signaling; PTPN1; endothelial dysfunction; hypoxia; pulmonary hypertension.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bone Morphogenetic Protein Receptors, Type II / genetics
Bone Morphogenetic Protein Receptors, Type II / metabolism
Endothelial Cells / metabolism
Humans
Hypertension, Pulmonary* / metabolism
Mice
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / genetics
Protein Tyrosine Phosphatase, Non-Receptor Type 1 / metabolism
Pulmonary Arterial Hypertension* / metabolism
Pulmonary Artery / metabolism
RNA, Small Interfering / metabolism
Vascular Diseases* / metabolism

Substances

BMPR2 protein, human
Bone Morphogenetic Protein Receptors, Type II
Protein Tyrosine Phosphatase, Non-Receptor Type 1
PTPN1 protein, human
RNA, Small Interfering
Ptpn1 protein, mouse
Bmpr2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding