Paracrine nitric oxide induces expression of cardiac sarcomeric proteins in adult progenitor cells through soluble guanylyl cyclase/cyclic-guanosine monophosphate and Wnt/β-catenin inhibition
| Autor: | Hrag Esfahani, Peter Brouckaert, Ann Friart, Adrien Strapart, Stefan Janssens, Pierre Sonveaux, Patrick Gilon, Aurelia De Pauw, Ruben Martherus, Belaid Sekkali, Paul Massion, Caroline Dubroca, Valéry Payen, Emilie Andre, Jean-Luc Balligand, Jana Kmecova, Catherine Sibille, Delphine De Mulder, Caroline Bouzin |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine Time Factors Physiology chemistry.chemical_compound Soluble Guanylyl Cyclase Antigens Ly Myocytes Cardiac Cyclic GMP Wnt Signaling Pathway Cells Cultured beta Catenin Mice Knockout biology GUCY1A3 Wnt signaling pathway Cell Differentiation Cell biology Nitric oxide synthase Adult Stem Cells Biochemistry cardiovascular system Female Cardiology and Cardiovascular Medicine Signal Transduction Sarcomeres Nitric Oxide Synthase Type III macromolecular substances Nitric Oxide Transfection Nitric oxide 03 medical and health sciences Paracrine signalling Physiology (medical) Paracrine Communication Animals Cell Lineage Nitric Oxide Donors Cyclic guanosine monophosphate Dose-Response Relationship Drug Immunomagnetic Separation technology industry and agriculture Membrane Proteins Coculture Techniques Mice Inbred C57BL 030104 developmental biology chemistry Catenin biology.protein Soluble guanylyl cyclase |
| Zdroj: | Cardiovascular Research. 112:478-490 |
| ISSN: | 1755-3245 0008-6363 |
| DOI: | 10.1093/cvr/cvw196 |
| Popis: | Aim Cardiac progenitor cells (CPC) from adult hearts can differentiate to several cell types composing the myocardium but the underlying molecular pathways are poorly characterized. We examined the role of paracrine nitric oxide (NO) in the specification of CPC to the cardiac lineage, particularly through its inhibition of the canonical Wnt/ β -catenin pathway, a critical step preceding cardiac differentiation. Methods and results Sca1 + CPC from adult mouse hearts were isolated by magnetic-activated cell sorting and clonally expanded. Pharmacologic NO donors increased their expression of cardiac myocyte-specific sarcomeric proteins in a concentration and time-dependent manner. The optimal time window for NO efficacy coincided with up-regulation of CPC expression of Gucy1a3 (coding the alpha1 subunit of guanylyl cyclase). The effect of paracrine NO was reproduced in vitro upon co-culture of CPC with cardiac myocytes expressing a transgenic NOS3 (endothelial nitric oxide synthase) and in vivo upon injection of CPC in infarcted hearts from cardiac-specific NOS3 transgenic mice. In mono- and co-cultures, this effect was abrogated upon inhibition of soluble guanylyl cyclase or nitric oxide synthase, and was lost in CPC genetically deficient in Gucy1a3 . Mechanistically, NO inhibits the constitutive activity of the canonical Wnt/ β -catenin in CPC and in cell reporter assays in a guanylyl cyclase-dependent fashion. This was paralleled with decreased expression of β -catenin and down-regulation of Wnt target genes in CPC and abrogated in CPC with a stabilized, non-inhibitable β -catenin. Conclusions Exogenous or paracrine sources of NO promote the specification towards the myocyte lineage and expression of cardiac sarcomeric proteins of adult CPC. This is contingent upon the expression and activity of the alpha1 subunit of guanylyl cyclase in CPC that is necessary for NO-mediated inhibition of the canonical Wnt/ β -catenin pathway. |
| Databáze: | OpenAIRE |
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