Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure

Vercauteren, Magali; Rémy, É.; Devaux, C; Dautreaux, Brigitte; Henry, Jean‐Paul; Bauer, Fabrice; Mulder, Paul; Huijsduijnen, Rob Hooft van; Bombrun, Agnès; Thuillez, Christian; Richard, Vincent

doi:10.1161/circulationaha.106.630129

Cited by 68 publications

(52 citation statements)

References 42 publications

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“…Moreover, PTP1B inhibitors enhance phosphorylation of Akt and endothelial NO synthase and improve peripheral endothelial dysfunction in a chronic heart failure model of mice. 25 This conflicting evidence may be attributable to differences in experimental conditions (cell culture conditions or transfection system with chimeric murine VEGFR2 or cell types or species). It is possible that PTP1B may preferentially bind to the VEGFR2-PLC␥ complex but not to the VEGFR2-phosphatidylinositol 3-kinase complex, which may form appropriate conformation Arrows indicate a low perfusion signal (dark blue) at immediately after operation (day 0) and a high perfusion signal (yellow to red) detected on day 7 in the ischemic hindlimbs.…”

Section: Nakamura Et Almentioning

confidence: 99%

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Nakamura

Patrushev

Inomata

et al. 2008

Circulation Research

161

145

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Abstract-Vascular endothelial growth factor (VEGF) binding induces phosphorylation of VEGF receptor (VEGFR)2 in tyrosine, which is followed by disruption of VE-cadherin-mediated cell-cell contacts of endothelial cells (ECs), thereby stimulating EC proliferation and migration to promote angiogenesis. Tyrosine phosphorylation events are controlled by the balance of activation of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Little is known about the role of endogenous PTPs in VEGF signaling in ECs. In this study, we found that PTP1B expression and activity are markedly increased in mice hindlimb ischemia model of angiogenesis. In ECs, overexpression of PTP1B, but not catalytically inactive mutant PTP1B-C/S, inhibits VEGF-induced phosphorylation of VEGFR2 and extracellular signal-regulated kinase 1/2, as well as EC proliferation, whereas knockdown of PTP1B by small interfering RNA enhances these responses, suggesting that PTP1B negatively regulates VEGFR2 signaling in ECs. VEGF-induced p38 mitogen-activated protein kinase phosphorylation and EC migration are not affected by PTP1B overexpression or knockdown. In vivo dephosphorylation and cotransfection assays reveal that PTP1B binds to VEGFR2 cytoplasmic domain in vivo and directly dephosphorylates activated VEGFR2 immunoprecipitates from human umbilical vein endothelial cells. Overexpression of PTP1B stabilizes VE-cadherin-mediated cell-cell adhesions by reducing VE-cadherin tyrosine phosphorylation, whereas PTP1B small interfering RNA causes opposite effects with increasing endothelial permeability, as measured by transendothelial electric resistance. In summary, PTP1B negatively regulates VEGFR2 receptor activation via binding to the VEGFR2, as well as stabilizes cell-cell adhesions through reducing tyrosine phosphorylation of VE-cadherin. Induction of PTP1B by hindlimb ischemia may represent an important counterregulatory mechanism that blunts overactivation of VEGFR2 during angiogenesis in vivo. (Circ Res. 2008;102:1182-1191.)Key Words: protein tyrosine phosphatase 1B Ⅲ vascular endothelial growth factor Ⅲ endothelial cell Ⅲ cell-cell adhesions Ⅲ angiogenesis

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Section: Nakamura Et Almentioning

confidence: 99%

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Nakamura

Patrushev

Inomata

et al. 2008

Circulation Research

161

145

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“…This was observed in terms of echography (increased LV FS and normalized E/A ratio) and invasive LV hemodynamics. In parallel, endothelial protection also triggered profound beneficial effects on LV remodeling, demonstrated by the decreased LV dilatation assessed by by guest on May 11, 2018 http://circheartfailure.ahajournals.org/ Downloaded from Endothelial Protection Reduces Heart Failure echography, together with decreased cardiac hypertrophy and fibrosis, and reduced cardiac ANP and BNP. We used the Tie2-Cre approach as it is known to be effective and potent for targeted gene deletion in the endothelium.…”

Section: Discussionmentioning

confidence: 99%

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure

Maupoint

Besnier

Gomez

et al. 2016

Circ: Heart Failure

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Background-Chronic heart failure (CHF) induces endothelial dysfunction in part because of decreased nitric oxide (NO • ) production, but the direct link between endothelial dysfunction and aggravation of CHF is not directly established. We previously reported that increased NO production via inhibition of protein tyrosine phosphatase 1B (PTP1B) is associated with reduced cardiac dysfunction in CHF. Investigation of the role of endothelial PTP1B in these effects may provide direct evidence of the link between endothelial dysfunction and CHF. Methods and Results-Endothelial deletion of PTP1B was obtained by crossing LoxP-PTP1B with Tie2-Cre mice. CHF was assessed 4 months after myocardial infarction. In some experiments, to exclude gene extinction in hematopoietic cells, Tie2-Cre/LoxP-PTP1B mice were lethally irradiated and reconstituted with bone marrow from wild-type mice, to obtain mouse with endothelial-specific deletion of PTP1B. Vascular function evaluated ex vivo in mesenteric arteries showed that in wild-type mice, CHF markedly impaired NO-dependent flow-mediated dilatation. CHF-induced endothelial dysfunction was less marked in endoPTP1B −/− mice, suggesting restored NO production. Echocardiographic, hemodynamic, and histological evaluations demonstrated that the selectively improved endothelial function was associated with reduced left ventricular dysfunction and remodeling, as well as increased survival, in the absence of signs of stimulated angiogenesis or increased cardiac perfusion. Conclusions-Prevention of endothelial dysfunction, by endothelial PTP1B deficiency, is sufficient to reduce cardiac dysfunction post myocardial infarction. Our results provide for the first time a direct demonstration that endothelial protection per se reduces CHF and further suggest a causal role for endothelial dysfunction in CHF development.(Circ Heart Fail. 2016;9:e002895.

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“…The restoration was inhibited by suppressing eNOS activity. Flow induced a transient eNOS phosphorylation that was absent in chronic heart failure and is, thus, suggested to be caused by changes in PTP1B activity (but not expression) (91). Evidence for the direct involvement of PTP1B in the pathophysiology mentioned earlier is unavailable, and controls for the involvement of other Cys-based PTPs were also undisclosed.…”

Section: Ptp-mediated Inhibition Of No Production In Chagas Diseasementioning

confidence: 95%

“…There is also a potential feedback loop consisting of several PTPs that are shown to directly or indirectly regulate the activity of NOSs, regulating either NOS tyrosine phosphorylation (coupled with changes in their activity) or transcriptional factors responsible for the NOS expression (6,12,16,25,35,36,38,44,65,77,85,87,91). The NOSs produce NO by a conversion of one of the terminal nitrogens of the guanidine group of L-arginine to NO, producing L-citrulline (37).…”

Section: Henebergmentioning

confidence: 99%

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

Heneberg

2014

Antioxidants & Redox Signaling

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Significance: Redox modifications of thiols serve as a molecular code enabling precise and complex regulation of protein tyrosine phosphatases (PTPs) and other proteins. Particular gasotransmitters and even the redox modifications themselves affect each other, of which a typical example is S-nitrosylation-mediated protection against the further oxidation of protein thiols. Recent Advances: For a long time, PTPs were considered constitutively active housekeeping enzymes. This view has changed substantially over the last two decades, and the PTP family is now recognized as a group of tightly and flexibly regulated fundamental enzymes. In addition to the conventional ways in which they are regulated, including noncovalent interactions, phosphorylation, and oxidation, the evidence that has accumulated during the past two decades suggests that many of these enzymes are also modulated by gasotransmitters, namely by nitric oxide (NO) and hydrogen sulfide (H 2 S). Critical Issues: The specificity and selectivity of the methods used to detect nitrosylation and sulfhydration remains to be corroborated, because several researchers raised the issue of false-positive results, particularly when using the most widespread biotin switch method. Further development of robust and straightforward proteomic methods is needed to further improve our knowledge of the full extent of the gasotransmitters-mediated changes in PTP activity, selectivity, and specificity. Further Directions: Results of the hitherto performed studies on gasotransmitter-mediated PTP signaling await translation into clinical medicine and pharmacotherapeutics. In addition to directly affecting the activity of particular PTPs, the use of reversible S-nitrosylation as a protective mechanism against oxidative stress should be of high interest. Antioxid. Redox Signal. 20, 2191-2209.

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Improvement of Peripheral Endothelial Dysfunction by Protein Tyrosine Phosphatase Inhibitors in Heart Failure

Cited by 68 publications

References 42 publications

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Role of Protein Tyrosine Phosphatase 1B in Vascular Endothelial Growth Factor Signaling and Cell–Cell Adhesions in Endothelial Cells

Selective Vascular Endothelial Protection Reduces Cardiac Dysfunction in Chronic Heart Failure

Reactive Nitrogen Species and Hydrogen Sulfide as Regulators of Protein Tyrosine Phosphatase Activity

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