Protein tyrosine phosphatase 1B regulates endothelial endoplasmic reticulum stress; role in endothelial dysfunction.

Abstract

Protein tyrosine phosphatase 1B (PTP1B) impairs nitric oxide (NO) production and induces endothelial dysfunction in various diseases, including diabetes, septic shock and heart failure. In non-cardiovascular tissues, PTP1B modulates endoplasmic reticulum stress (ERS) however this role has never been assessed in endothelial cells. We evaluated the link between PTP1B, ERS and endothelial dysfunction in mice. Induction of ERS (Tunicamycin) in vivo in mice or ex vivo in mouse arteries led to severe arterial endothelial dysfunction (i.e. reduced flow-dependent, NO mediated dilatation in isolated small mesenteric arteries), and this was prevented by the PTP1B inhibitor trodusquemine and absent in PTP1B-/- mice. Trodusquemine also prevented the Tunicamycin -induced increased arterial levels of the molecular ERS actors 78 kDa glucose-regulated protein (GRP78) and Activating Transcription Factor 6 (ATF6α). Tunicamycin strongly increased the interactions of PTP1B with GRP78 and the activated forms of protein kinase RNA-like endoplasmic reticulum kinase (PERK) and IRE1α (proximity Ligation Assay). Thus, PTP1B plays a central role in the regulation of ERS in the endothelium, and the endothelial protective effect of PTP1B inhibition appears likely due at least in part to reduction of endothelial ERS, notably by promoting PERK protective pathway. Modulation of ER stress via PTP1B inhibitors may be a promising approach to protect the endothelium in cardiovascular diseases.

• Authors: Pierre-Alain Thiebaut, Eugénie Delile, David Coquerel, Jean-Michel Brunel, Sylvanie Renet, Fabienne Tamion, Vincent Richard
• Journal: Vascular pharmacology (Vascul Pharmacol) Vol. 109 Pg. 36-44 (10 2018) ISSN: 1879-3649 [Electronic] United States
• PMID: 29894845 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Inc. All rights reserved.

Chemical References

• 3-N-1(spermine)-7, 24-dihydroxy-5-cholestane 24-sulfate
• Activating Transcription Factor 6
• Atf6 protein, mouse
• Cholestanes
• Endoplasmic Reticulum Chaperone BiP
• Enzyme Inhibitors
• Heat-Shock Proteins
• Hspa5 protein, mouse
• Tunicamycin
• Spermine
• Nitric Oxide
• Ern1 protein, mouse
• PERK kinase
• Protein Serine-Threonine Kinases
• eIF-2 Kinase
• Endoribonucleases
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Ptpn1 protein, mouse

Topics

• Activating Transcription Factor 6 (metabolism)
• Animals
• Cholestanes (pharmacology)
• Endoplasmic Reticulum Chaperone BiP
• Endoplasmic Reticulum Stress (drug effects)
• Endoribonucleases (metabolism)
• Endothelium, Vascular (drug effects, enzymology, physiopathology)
• Enzyme Inhibitors (pharmacology)
• Heat-Shock Proteins (metabolism)
• Male
• Mice, Inbred BALB C
• Mice, Knockout
• Nitric Oxide (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (antagonists & inhibitors, deficiency, genetics, metabolism)
• Signal Transduction (drug effects)
• Spermine (analogs & derivatives, pharmacology)
• Tunicamycin (pharmacology)
• Vasodilation (drug effects)
• eIF-2 Kinase (metabolism)