β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
- Imperial College London, United Kingdom
- University of Würzburg, Germany
- Université Catholique de Louvain, Belgium
- Universitätsklinikum Hamburg Eppendorf, Germany
Abstract
Cardiomyocyte b3-adrenoceptors (b3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3',5'-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of b3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase 2 dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the b3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files. Source data files are provided for all figures to eLife journal.
Article and author information
Author details
Sophie Schobesberger
Funding
British Heart Foundation (12/18/30088)
- Julia Gorelik
Wellcome (WT090594)
- Julia Gorelik
Deutsche Forschungsgemeinschaft (Fr 1725/3-2)
- Andreas Friebe
- Viacheslav O Nikolaev
National Institutes of Health (ROI-HL grant 126802)
- Julia Gorelik
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures performed in the UK were carried out according to the standards for the care and use of animal subjects determined by the UK Home Office (ASPA1986 Amendments Regulations 2012) incorporating the EU directive 2010/63/EU. The Animal Welfare and Ethical Review Body Committee of Imperial College London approved all protocols.The parts of the investigation, which were performed in Germany, conformed to the guide for the care and use of laboratory animals published by the National Institutes of Health (Bethesda, Maryland; Publication No. 85-23, revised 2011, published by National Research Council, Washington, D.C.). The experimental procedures were in accordance with the German Law for the Protection of Animals and with the guidelines of the European Community.
Copyright
© 2020, Schobesberger et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 1,271
- views
-
- 214
- downloads
-
- 29
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
β3-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes
eLife 9:e52221.
https://doi.org/10.7554/eLife.52221
Further reading
-
- Cell Biology
- Chromosomes and Gene Expression
During oncogene-induced senescence there are striking changes in the organisation of heterochromatin in the nucleus. This is accompanied by activation of a pro-inflammatory gene expression programme – the senescence-associated secretory phenotype (SASP) – driven by transcription factors such as NF-κB. The relationship between heterochromatin re-organisation and the SASP has been unclear. Here, we show that TPR, a protein of the nuclear pore complex basket required for heterochromatin re-organisation during senescence, is also required for the very early activation of NF-κB signalling during the stress-response phase of oncogene-induced senescence. This is prior to activation of the SASP and occurs without affecting NF-κB nuclear import. We show that TPR is required for the activation of innate immune signalling at these early stages of senescence and we link this to the formation of heterochromatin-enriched cytoplasmic chromatin fragments thought to bleb off from the nuclear periphery. We show that HMGA1 is also required for cytoplasmic chromatin fragment formation. Together these data suggest that re-organisation of heterochromatin is involved in altered structural integrity of the nuclear periphery during senescence, and that this can lead to activation of cytoplasmic nucleic acid sensing, NF-κB signalling, and activation of the SASP.
-
- Cell Biology
- Medicine
The IncRNA Malat1 was initially believed to be dispensable for physiology due to the lack of observable phenotypes in Malat1 knockout (KO) mice. However, our study challenges this conclusion. We found that both Malat1 KO and conditional KO mice in the osteoblast lineage exhibit significant osteoporosis. Mechanistically, Malat1 acts as an intrinsic regulator in osteoblasts to promote osteogenesis. Interestingly, Malat1 does not directly affect osteoclastogenesis but inhibits osteoclastogenesis in a non-autonomous manner in vivo via integrating crosstalk between multiple cell types, including osteoblasts, osteoclasts, and chondrocytes. Our findings substantiate the existence of a novel remodeling network in which Malat1 serves as a central regulator by binding to β-catenin and functioning through the β-catenin-OPG/Jagged1 pathway in osteoblasts and chondrocytes. In pathological conditions, Malat1 significantly promotes bone regeneration in fracture healing. Bone homeostasis and regeneration are crucial to well-being. Our discoveries establish a previous unrecognized paradigm model of Malat1 function in the skeletal system, providing novel mechanistic insights into how a lncRNA integrates cellular crosstalk and molecular networks to fine tune tissue homeostasis, remodeling and repair.
