Synthase. Archives - World Asthma Foundation

Bidirectional Cross-Regulation between the Endothelial Nitric Oxide Synthase and ?-Catenin Signaling Pathways.

Cardiovasc Res. 2014 Jul 25;

Authors: Warboys CM, Chen N, Zhang Q, Shaifta Y, Vanderslott G, Passacquale G, Hu Y, Xu Q, Ward JP, Ferro A

Abstract
AIMS: ?-catenin has been shown to be regulated by inducible nitric oxide synthase (NOS) in endothelial cells. We investigated here whether ?-catenin interacts with and regulates endothelial NOS (eNOS) and whether eNOS activation promotes ?-catenin signaling.
METHODS AND RESULTS: We identified ?-catenin as a novel eNOS binding protein in human umbilical vein endothelial cells (HUVECs) by mass spectroscopy and western blot analyses of ?-catenin and eNOS immunoprecipitates. This was confirmed by in situ proximity ligation assay. eNOS activity, assessed by cGMP production and eNOS phosphorylation (Ser1177), was enhanced in ?-catenin(-/-) mouse pulmonary endothelial cells (MPECs) relative to wild type MPECs. eNOS activation (using adenosine, salbutamol, thrombin or histamine), or application of an NO donor (spermine NONOate) or cGMP-analogue (8-bromo-cGMP) caused nuclear translocation of ?-catenin in HUVEC as shown by western blotting of nuclear extracts. Exposure to spermine NONOate, 8-bromo-cGMP or sildenafil (a phosphodiesterase type 5 inhibitor) also increased the expression of ?-catenin-dependent transcripts, IL-8 and cyclin D1. Stimulation of wild type MPECs with basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), spermine NONOate, 8-bromo-cGMP or sildenafil increased tube length relative to controls in an angiogenesis assay. These responses were abrogated in ?-catenin(-/-) MPECs, with the exception of that to bFGF which is NO-independent. In C57BL/6 mice, subcutaneous VEGF-supplemented Matrigel plugs containing ?-catenin(-/-) MPECs exhibited reduced angiogenesis compared to plugs containing wild type MPECs. Angiogenesis was not altered in bFGF-supplemented Matrigel.
CONCLUSIONS: These data reveal bidirectional cross talk and regulation between the NO-cGMP and ?-catenin signaling pathways.

PMID: 25062958 [PubMed – as supplied by publisher]

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Grape Seed Proanthocyanidin Extract Attenuates Airway Inflammation and Hyperresponsiveness in a Murine Model of Asthma by Downregulating Inducible Nitric Oxide Synthase.

Planta Med. 2011 Mar 30;

Authors: Zhou DY, Du Q, Li RR, Huang M, Zhang Q, Wei GZ

Allergic asthma is characterized by hyperresponsiveness and inflammation of the airway with increased expression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide (NO). Grape seed proanthocyanidin extract (GSPE) has been proved to have antioxidant, antitumor, anti-inflammatory, and other pharmacological effects. The purpose of this study was to examine the role of GSPE on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice, sensitized and challenged with ovalbumin (OVA), were intraperitoneally injected with GSPE. Administration of GSPE remarkably suppressed airway resistance and reduced the total inflammatory cell and eosinophil counts in BALF. Treatment with GSPE significantly enhanced the interferon (IFN)- ? level and decreased interleukin (IL)-4 and IL-13 levels in BALF and total IgE levels in serum. GSPE also attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. The elevated iNOS expression observed in the OVA mice was significantly inhibited by GSPE. In conclusion, GSPE decreases the progression of airway inflammation and hyperresponsiveness by downregulating the iNOS expression, promising to have a potential in the treatment of allergic asthma.

PMID: 21452107 [PubMed – as supplied by publisher]

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