PMID- 34296297 OWN - NLM STAT- MEDLINE DCOM- 20211109 LR - 20211109 IS - 1791-3004 (Electronic) IS - 1791-2997 (Linking) VI - 24 IP - 3 DP - 2021 Sep TI - Protein tyrosine phosphatase 1B inhibition improves endoplasmic reticulum stress‑impaired endothelial cell angiogenic response: A critical role for cell survival. LID - 665 [pii] LID - 10.3892/mmr.2021.12304 [doi] AB - Endoplasmic reticulum (ER) stress contributes to endothelial dysfunction, which is the initial step in atherogenesis. Blockade of protein tyrosine phosphatase (PTP)1B, a negative regulator of insulin receptors that is critically located on the surface of ER membrane, has been found to improve endothelial dysfunction. However, the role of ER stress and its related apoptotic sub‑pathways in PTP1B‑mediated endothelial dysfunction, particularly its angiogenic capacity, have not yet been fully elucidated. Thus, the present study aimed to investigate the impact of PTP1B suppression on ER stress‑mediated impaired angiogenesis and examined the contribution of apoptotic signals in this process. Endothelial cells were exposed to pharmacological ER stressors, including thapsigargin (TG) or 1,4‑dithiothreitol (DTT), in the presence or absence of a PTP1B inhibitor or small interfering (si)RNA duplexes. Then, ER stress, angiogenic capacity, cell cycle, apoptosis and the activation of key apoptotic signals were assessed. It was identified that the inhibition of PTP1B prevented ER stress caused by DTT and TG. Moreover, ER stress induction impaired the activation of endothelial nitric oxide synthase (eNOS) and the angiogenic capacity of endothelial cells, while PTP1B inhibition exerted a protective effect. The results demonstrated that blockade or knockdown of PTP1B prevented ER stress‑induced apoptosis and cell cycle arrest. This effect was associated with reduced expression levels of caspase‑12 and poly (ADP‑Ribose) polymerase 1. PTP1B blockade also suppressed autophagy activated by TG. The current data support the critical role of PTP1B in ER stress‑mediated endothelial dysfunction, characterized by reduced angiogenic capacity, with an underlying mechanism involving reduced eNOS activation and cell survival. These findings provide evidence of the therapeutic potential of targeting PTP1B in cardiovascular ischemic conditions. FAU - Abdelsalam, Shahenda S AU - Abdelsalam SS AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Pasha, Mazhar AU - Pasha M AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - El-Gamal, Heba AU - El-Gamal H AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Hasan, Maram AU - Hasan M AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Elrayess, Mohamed A AU - Elrayess MA AD - Biomedical Research Center, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Zeidan, Asad AU - Zeidan A AD - Biomedical and Pharmaceutical Research Unit, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Korashy, Hesham M AU - Korashy HM AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. FAU - Agouni, Abdelali AU - Agouni A AD - Department of Pharmaceutical Sciences, College of Pharmacy, QU Health, Qatar University, P.O. Box 2713 Doha, Qatar. LA - eng PT - Journal Article DEP - 20210723 PL - Greece TA - Mol Med Rep JT - Molecular medicine reports JID - 101475259 RN - 0 (ATF4 protein, human) RN - 0 (CCL2 protein, human) RN - 0 (CXCL8 protein, human) RN - 0 (Chemokine CCL2) RN - 0 (DDIT3 protein, human) RN - 0 (Heat-Shock Proteins) RN - 0 (ICAM1 protein, human) RN - 0 (IL6 protein, human) RN - 0 (Interleukin-6) RN - 0 (Interleukin-8) RN - 0 (Membrane Glycoproteins) RN - 0 (endoplasmin) RN - 126547-89-5 (Intercellular Adhesion Molecule-1) RN - 145891-90-3 (Activating Transcription Factor 4) RN - 147336-12-7 (Transcription Factor CHOP) RN - 67526-95-8 (Thapsigargin) RN - EC 1.14.13.39 (NOS3 protein, human) RN - EC 1.14.13.39 (Nitric Oxide Synthase Type III) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 3.1.3.48 (PTPN1 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 1) RN - T8ID5YZU6Y (Dithiothreitol) SB - IM MH - Activating Transcription Factor 4/genetics/metabolism MH - Apoptosis/drug effects/genetics MH - Autophagy/drug effects/genetics MH - Cell Survival/drug effects/genetics MH - Chemokine CCL2/genetics/metabolism MH - Dithiothreitol/pharmacology MH - *Endoplasmic Reticulum Stress/drug effects MH - Endothelial Cells/drug effects/*metabolism MH - Heat-Shock Proteins/genetics/metabolism MH - Human Umbilical Vein Endothelial Cells MH - Humans MH - Intercellular Adhesion Molecule-1/genetics/metabolism MH - Interleukin-6/genetics/metabolism MH - Interleukin-8/genetics/metabolism MH - Membrane Glycoproteins/genetics/metabolism MH - Neovascularization, Physiologic/drug effects MH - Nitric Oxide Synthase Type III/metabolism MH - Protein Tyrosine Phosphatase, Non-Receptor Type 1/*antagonists & inhibitors/*genetics MH - Proto-Oncogene Proteins c-akt/metabolism MH - Thapsigargin/pharmacology MH - Transcription Factor CHOP/genetics/metabolism OTO - NOTNLM OT - angiogenesis OT - apoptosis OT - endoplasmic reticulum stress OT - endothelial dysfunction OT - protein tyrosine phosphatase 1B OT - tyrosine phosphatases EDAT- 2021/07/24 06:00 MHDA- 2021/11/10 06:00 CRDT- 2021/07/23 07:00 PHST- 2021/04/03 00:00 [received] PHST- 2021/06/28 00:00 [accepted] PHST- 2021/07/23 07:00 [entrez] PHST- 2021/07/24 06:00 [pubmed] PHST- 2021/11/10 06:00 [medline] AID - 665 [pii] AID - 10.3892/mmr.2021.12304 [doi] PST - ppublish SO - Mol Med Rep. 2021 Sep;24(3):665. doi: 10.3892/mmr.2021.12304. Epub 2021 Jul 23.