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

Abstract

Increased endothelial cell (EC) apoptosis is associated with the development of atherosclerotic plaques that develop predominantly at sites exposed to disturbed flow (DF). Strategies to promote EC 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 ECs as we previously demonstrated. Here we investigated the physiological role of β-catenin as a mediator of NO-induced cell survival in ECs. We found that β-catenin depleted human umbilical vein ECs (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 levels compared to control cells in static cultures. In addition, β-catenin depletion abrogated the protective effects of the NO donor, Snitroso-N-acetylpenicillamine, during TNFα-and H 2 O 2-induced apoptosis. Using an orbital shaker to generate shear stress, we confirmed eNOS and β-catenin interaction in HUVEC exposed to undisturbed flow and 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 ECs. sGC activity and β-catenin-dependent transcription of Bcl-2, survivin, BIRC3 and eNOS are essential to maintain cell survival in ECs under DF.

<em>Agaricus blazei</em> extract (FA‑2‑b‑&beta;) induces apoptosis in chronic myeloid leukemia cells

“…Thus, the results of the present study suggest that the anti-tumor activity of AbM may be due to decreased cellular proliferation, but also the induction of cell apoptosis (54). This is supported by other studies that demonstrate that anti-cancer agents regulate Bcl-2 family members (including Bax or Bcl-2) (55)(56)(57). This evidence strongly supports the results of the present study, which demonstrated that FA-2-b-β induced leukemia cell apoptosis in vitro, accompanied by elevated Bax expression and decreased level of Bcl-2.…”

Paradoxical Pro-angiogenic Effect of Low-Dose Ellipticine Identified by In Silico Drug Repurposing

“…Despite a high degree of similarity and functional overlap, these isoforms are not functionally identical and redundant. It is known whether GSK-3β plays a central role in various signaling pathways, such as the Wnt/β-catenin, Hedgehog, Notch, and insulin signaling pathways [41][42][43][44][45] The possible pro-angiogenic mechanism for low concentrations of ellipticine is as follows: β-catenin has a positive effect on the serine/threonine-specific protein kinase-mechanistic target of rapamycin (AKT-mTOR) pathway [37], thereby inducing endothelial nitric oxide synthase (eNOS) expression and increasing nitric oxide (NO) [46]. Additionally, an activated AKT enhances the expression of hypoxia-inducible factor-1α (HIF-1α), which has a great influence on the increase in vascular endothelial growth factor (VEGF) [47].…”

Developmental programming in human umbilical cord vein endothelial cells following fetal growth restriction

“…However, higher or no difference in Gal-1 expression was observed in term placentas from pregnancies complicated by respectively preeclampsia or FGR [32,33]. Considering the different histopathology between early-onset and late-onset FGR (or preeclampsia), the downregulated LGALS1 expression in early-onset FGR speculatively contributes directly to placental insufficiency, while the upregulated expression observed in late-onset FGR might be secondary to relative placental-umbilical hypoxia or reduced umbilical flow [30,32,34]. Gal-1 has been suggested as an early marker of endothelial dysfunction, and dysregulated Gal-1 has been linked to poor blood pressure regulation and development of cardiovascular disease [27,28].…”