β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

Virginia Tajadura; Marie Haugsten Hansen; Joy Smith; Hannah Charles; Matthew Rickman; Keith Farrell-Dillon; Vasco Claro; Christina Warboys; Albert Ferro

doi:10.1038/s41419-020-2687-6

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

Virginia Tajadura, Marie Haugsten Hansen, Joy Smith, Hannah Charles, Matthew Rickman, Keith Farrell-Dillon, Vasco Claro, Christina Warboys, Albert Ferro

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Abstract

Increased endothelial cell apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow. Strategies to promote endothelial cell survival may therefore represent a novel therapeutic approach in cardiovascular disease. Nitric oxide (NO) and β-catenin have both been shown to promote cell survival and they interact in endothelial cells as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in endothelial cells. We found that β-catenin depleted human umbilical vein endothelial cells (HUVEC) stimulated with pharmacological activators of endothelial NO synthase (eNOS) showed a reduction in eNOS phosphorylation (Ser1177) as well as reduced intracellular cyclic guanosine monophosphate (cGMP) levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, SNAP, during TNFα- and H2O2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow (UF) and disturbed flow (DF) and showed that β-catenin depletion reduced eNOS phosphorylation. β- catenin depletion promoted apoptosis exclusively in HUVEC exposed to DF as did inhibition of soluble guanylate cyclase (sGC) or β-catenin transcriptional activity. The expression of the pro-survival genes, Bcl-2 and survivin was also reduced following inhibition of β-catenin transcriptional activity, as was the expression of eNOS. In conclusion, our data demonstrate that β-catenin is a positive regulator of eNOS activity and cell survival in human endothelial cells. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in endothelial cells under DF.

Original language	English
Article number	493
Number of pages	16
Journal	Cell Death & Disease
Volume	11
Early online date	30 Jun 2020
DOIs	https://doi.org/10.1038/s41419-020-2687-6
Publication status	Published - 30 Jun 2020

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β-catenin promotes endothelial survival_TAJADURA_Accepted15June2020_GOLD AAMAccepted author manuscript, 0.99 MBLicence: CC BY
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title = "β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression",

abstract = "Increased endothelial cell apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow. Strategies to promote endothelial cell survival may therefore represent a novel therapeutic approach in cardiovascular disease. Nitric oxide (NO) and β-catenin have both been shown to promote cell survival and they interact in endothelial cells as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in endothelial cells. We found that β-catenin depleted human umbilical vein endothelial cells (HUVEC) stimulated with pharmacological activators of endothelial NO synthase (eNOS) showed a reduction in eNOS phosphorylation (Ser1177) as well as reduced intracellular cyclic guanosine monophosphate (cGMP) levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, SNAP, during TNFα- and H2O2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow (UF) and disturbed flow (DF) and showed that β-catenin depletion reduced eNOS phosphorylation. β- catenin depletion promoted apoptosis exclusively in HUVEC exposed to DF as did inhibition of soluble guanylate cyclase (sGC) or β-catenin transcriptional activity. The expression of the pro-survival genes, Bcl-2 and survivin was also reduced following inhibition of β-catenin transcriptional activity, as was the expression of eNOS. In conclusion, our data demonstrate that β-catenin is a positive regulator of eNOS activity and cell survival in human endothelial cells. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in endothelial cells under DF.",

author = "Virginia Tajadura and {Haugsten Hansen}, Marie and Joy Smith and Hannah Charles and Matthew Rickman and Keith Farrell-Dillon and Vasco Claro and Christina Warboys and Albert Ferro",

year = "2020",

month = jun,

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doi = "10.1038/s41419-020-2687-6",

language = "English",

volume = "11",

journal = "Cell Death & Disease",

issn = "2041-4889",

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T1 - β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

AU - Tajadura, Virginia

AU - Haugsten Hansen, Marie

AU - Smith, Joy

AU - Charles, Hannah

AU - Rickman, Matthew

AU - Farrell-Dillon, Keith

AU - Claro, Vasco

AU - Warboys, Christina

AU - Ferro, Albert

PY - 2020/6/30

Y1 - 2020/6/30

N2 - Increased endothelial cell apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow. Strategies to promote endothelial cell survival may therefore represent a novel therapeutic approach in cardiovascular disease. Nitric oxide (NO) and β-catenin have both been shown to promote cell survival and they interact in endothelial cells as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in endothelial cells. We found that β-catenin depleted human umbilical vein endothelial cells (HUVEC) stimulated with pharmacological activators of endothelial NO synthase (eNOS) showed a reduction in eNOS phosphorylation (Ser1177) as well as reduced intracellular cyclic guanosine monophosphate (cGMP) levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, SNAP, during TNFα- and H2O2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow (UF) and disturbed flow (DF) and showed that β-catenin depletion reduced eNOS phosphorylation. β- catenin depletion promoted apoptosis exclusively in HUVEC exposed to DF as did inhibition of soluble guanylate cyclase (sGC) or β-catenin transcriptional activity. The expression of the pro-survival genes, Bcl-2 and survivin was also reduced following inhibition of β-catenin transcriptional activity, as was the expression of eNOS. In conclusion, our data demonstrate that β-catenin is a positive regulator of eNOS activity and cell survival in human endothelial cells. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in endothelial cells under DF.

AB - Increased endothelial cell apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow. Strategies to promote endothelial cell survival may therefore represent a novel therapeutic approach in cardiovascular disease. Nitric oxide (NO) and β-catenin have both been shown to promote cell survival and they interact in endothelial cells as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in endothelial cells. We found that β-catenin depleted human umbilical vein endothelial cells (HUVEC) stimulated with pharmacological activators of endothelial NO synthase (eNOS) showed a reduction in eNOS phosphorylation (Ser1177) as well as reduced intracellular cyclic guanosine monophosphate (cGMP) levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, SNAP, during TNFα- and H2O2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow (UF) and disturbed flow (DF) and showed that β-catenin depletion reduced eNOS phosphorylation. β- catenin depletion promoted apoptosis exclusively in HUVEC exposed to DF as did inhibition of soluble guanylate cyclase (sGC) or β-catenin transcriptional activity. The expression of the pro-survival genes, Bcl-2 and survivin was also reduced following inhibition of β-catenin transcriptional activity, as was the expression of eNOS. In conclusion, our data demonstrate that β-catenin is a positive regulator of eNOS activity and cell survival in human endothelial cells. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in endothelial cells under DF.

U2 - 10.1038/s41419-020-2687-6

DO - 10.1038/s41419-020-2687-6

M3 - Article

SN - 2041-4889

VL - 11

JO - Cell Death & Disease

JF - Cell Death & Disease

M1 - 493

ER -

β-catenin promotes endothelial survival by regulating eNOS activity and flow-dependent anti-apoptotic gene expression

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