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Enhanced arginine metabolism may counteract inflammation pathways in asthma
Science Codex High arginine levels are often observed in asthmatic individuals and may support increased production of nitric oxide, which is known to worsen airway inflammation. Medications that reduce arginine availability do not effectively treat asthma … |
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Study reveals new insights into how asthma 'pathways' could be blocked
Medical Xpress Asthma affects about five million people in the UK. Not all patients respond the same way to current treatments, suggesting that asthma is more than a single disease. Drugs that target specific molecules in the lungs suggest that the typical symptoms … |
View full post on asthma – Google News
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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Emergence of airway smooth muscle mechanical behaviour through dynamic reorganisation of contractile units and force transmission pathways.
J Appl Physiol (1985). 2014 Jan 30;
Authors: Brook BS
Abstract
Airway hyper-responsiveness (AHR) in asthma remains poorly understood despite significant research effort to elucidate relevant underlying mechanisms. In particular, a significant body of experimental work has focussed on the effect of tidal fluctuations on airway smooth muscle (ASM) cells, tissues, lung slices and whole airways in order to understand the bronchodilating effect of tidal breathing and deep inspirations. These studies have motivated conceptual models that involve dynamic reorganisation of both cytoskeletal components as well contractile machinery. In this paper, a biophysical model of the whole ASM cell is presented which combines (i) crossbridge cycling between actin and myosin, (ii) actin-myosin disconnectivity, under imposed length changes, to allow dynamic reconfiguration of “force transmission pathways” and (iii) dynamic parallel-to-serial transitions of contractile units within these pathways, that occur through a length fluctuation. Results of this theoretical model suggest that behaviour characteristic of experimentally observed force-length loops of maximally activated ASM strips can be explained by interactions between the three mechanisms. Crucially, both sustained disconnectivity and parallel-to-serial transitions are necessary to explain the nature of hysteresis and strain-stiffening observed experimentally. The results provide strong evidence that dynamic rearrangement of contractile machinery is a likely mechanism underlying many of the phenomena observed at timescales associated with tidal breathing. This theoretical cell-level model captures many of the salient features of mechanical behaviour observed experimentally and should provide a useful starting block for a bottom-up approach to understanding tissue-level mechanical behaviour.
PMID: 24481961 [PubMed – as supplied by publisher]
View full post on pubmed: asthma