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
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 throu...
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| Veröffentlicht in: | Cardiovascular research 2016-10, Vol.112 (1), p.478-490 |
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| creator | De Pauw, Aurelia Massion, Paul Sekkali, Belaid Andre, Emilie Dubroca, Caroline Kmecova, Jana Bouzin, Caroline Friart, Ann Sibille, Catherine Gilon, Patrick De Mulder, Delphine Esfahani, Hrag Strapart, Adrien Martherus, Ruben Payen, Valéry Sonveaux, Pierre Brouckaert, Peter Janssens, Stefan Balligand, Jean-Luc |
| description | 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.
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.
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. |
| doi_str_mv | 10.1093/cvr/cvw196 |
| format | Article |
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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.
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.</description><identifier>ISSN: 0008-6363</identifier><identifier>EISSN: 1755-3245</identifier><identifier>DOI: 10.1093/cvr/cvw196</identifier><identifier>PMID: 27520736</identifier><language>eng</language><publisher>England</publisher><subject>Adult Stem Cells - drug effects ; Adult Stem Cells - metabolism ; Animals ; Antigens, Ly - metabolism ; beta Catenin - genetics ; beta Catenin - metabolism ; Cell Differentiation - drug effects ; Cell Lineage ; Cells, Cultured ; Coculture Techniques ; Cyclic GMP - metabolism ; Dose-Response Relationship, Drug ; Female ; Immunomagnetic Separation ; Male ; Membrane Proteins - metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac - drug effects ; Myocytes, Cardiac - enzymology ; Nitric Oxide - metabolism ; Nitric Oxide Donors - pharmacology ; Nitric Oxide Synthase Type III - genetics ; Nitric Oxide Synthase Type III - metabolism ; Paracrine Communication - drug effects ; Sarcomeres - drug effects ; Sarcomeres - enzymology ; Signal Transduction ; Soluble Guanylyl Cyclase - deficiency ; Soluble Guanylyl Cyclase - genetics ; Soluble Guanylyl Cyclase - metabolism ; Time Factors ; Transfection ; Wnt Signaling Pathway - drug effects</subject><ispartof>Cardiovascular research, 2016-10, Vol.112 (1), p.478-490</ispartof><rights>Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c323t-cc13968cd2dff02fce1a47dcf2e3e17edadce7487548a0ab0f69ae1f7a6429973</citedby><cites>FETCH-LOGICAL-c323t-cc13968cd2dff02fce1a47dcf2e3e17edadce7487548a0ab0f69ae1f7a6429973</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27520736$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>De Pauw, Aurelia</creatorcontrib><creatorcontrib>Massion, Paul</creatorcontrib><creatorcontrib>Sekkali, Belaid</creatorcontrib><creatorcontrib>Andre, Emilie</creatorcontrib><creatorcontrib>Dubroca, Caroline</creatorcontrib><creatorcontrib>Kmecova, Jana</creatorcontrib><creatorcontrib>Bouzin, Caroline</creatorcontrib><creatorcontrib>Friart, Ann</creatorcontrib><creatorcontrib>Sibille, Catherine</creatorcontrib><creatorcontrib>Gilon, Patrick</creatorcontrib><creatorcontrib>De Mulder, Delphine</creatorcontrib><creatorcontrib>Esfahani, Hrag</creatorcontrib><creatorcontrib>Strapart, Adrien</creatorcontrib><creatorcontrib>Martherus, Ruben</creatorcontrib><creatorcontrib>Payen, Valéry</creatorcontrib><creatorcontrib>Sonveaux, Pierre</creatorcontrib><creatorcontrib>Brouckaert, Peter</creatorcontrib><creatorcontrib>Janssens, Stefan</creatorcontrib><creatorcontrib>Balligand, Jean-Luc</creatorcontrib><title>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</title><title>Cardiovascular research</title><addtitle>Cardiovasc Res</addtitle><description>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.
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.
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.</description><subject>Adult Stem Cells - drug effects</subject><subject>Adult Stem Cells - metabolism</subject><subject>Animals</subject><subject>Antigens, Ly - metabolism</subject><subject>beta Catenin - genetics</subject><subject>beta Catenin - metabolism</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Lineage</subject><subject>Cells, Cultured</subject><subject>Coculture Techniques</subject><subject>Cyclic GMP - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Female</subject><subject>Immunomagnetic Separation</subject><subject>Male</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myocytes, Cardiac - drug effects</subject><subject>Myocytes, Cardiac - enzymology</subject><subject>Nitric Oxide - metabolism</subject><subject>Nitric Oxide Donors - pharmacology</subject><subject>Nitric Oxide Synthase Type III - genetics</subject><subject>Nitric Oxide Synthase Type III - metabolism</subject><subject>Paracrine Communication - drug effects</subject><subject>Sarcomeres - drug effects</subject><subject>Sarcomeres - enzymology</subject><subject>Signal Transduction</subject><subject>Soluble Guanylyl Cyclase - deficiency</subject><subject>Soluble Guanylyl Cyclase - genetics</subject><subject>Soluble Guanylyl Cyclase - metabolism</subject><subject>Time Factors</subject><subject>Transfection</subject><subject>Wnt Signaling Pathway - drug effects</subject><issn>0008-6363</issn><issn>1755-3245</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kcGO1DAMhiMEYoeFCw-AckRIZZKmbdojWi0s0kpwAHGsPI47DWqTkqTLzmvxBDwBz0SqWThYlq3Pv239jL2U4q0UndrjXcjxU3bNI7aTuq4LVVb1Y7YTQrRFoxp1wZ7F-D2Xda2rp-yi1HUptGp27PdnCIDBOuLOpmCR-3triFtnVqTI6X4JFKP1jvuBIwRjAXmEgH6mDV-CT2RdzBMczDqlrXOkLOYDR5qmyNMY_HocefTTepiIH1dwp-k0cTzhBJH2W7ZYbH0ft1Nm7_wy-riMkIiDM_ybS_s_vwrMtcubrBvtwaZ81nP2ZIAp0ouHfMm-vr_-cnVT3H768PHq3W2BqlSpQJSqa1o0pRkGUQ5IEiptcChJkdRkwCDpqtV11YKAgxiaDkgOGpqq7DqtLtnrs25-78dKMfWzjdt_4MivsZdtqYQSnVAZfXNGMfgYAw39EuwM4dRL0W-O9dmx_uxYhl896K6Hmcx_9J9F6i9Wzps3</recordid><startdate>201610</startdate><enddate>201610</enddate><creator>De Pauw, Aurelia</creator><creator>Massion, Paul</creator><creator>Sekkali, Belaid</creator><creator>Andre, Emilie</creator><creator>Dubroca, Caroline</creator><creator>Kmecova, Jana</creator><creator>Bouzin, Caroline</creator><creator>Friart, Ann</creator><creator>Sibille, Catherine</creator><creator>Gilon, Patrick</creator><creator>De Mulder, Delphine</creator><creator>Esfahani, Hrag</creator><creator>Strapart, Adrien</creator><creator>Martherus, Ruben</creator><creator>Payen, Valéry</creator><creator>Sonveaux, Pierre</creator><creator>Brouckaert, Peter</creator><creator>Janssens, Stefan</creator><creator>Balligand, Jean-Luc</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope></search><sort><creationdate>201610</creationdate><title>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</title><author>De Pauw, Aurelia ; Massion, Paul ; Sekkali, Belaid ; Andre, Emilie ; Dubroca, Caroline ; Kmecova, Jana ; Bouzin, Caroline ; Friart, Ann ; Sibille, Catherine ; Gilon, Patrick ; De Mulder, Delphine ; Esfahani, Hrag ; Strapart, Adrien ; Martherus, Ruben ; Payen, Valéry ; Sonveaux, Pierre ; Brouckaert, Peter ; Janssens, Stefan ; Balligand, Jean-Luc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c323t-cc13968cd2dff02fce1a47dcf2e3e17edadce7487548a0ab0f69ae1f7a6429973</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adult Stem Cells - drug effects</topic><topic>Adult Stem Cells - metabolism</topic><topic>Animals</topic><topic>Antigens, Ly - metabolism</topic><topic>beta Catenin - genetics</topic><topic>beta Catenin - metabolism</topic><topic>Cell Differentiation - drug effects</topic><topic>Cell Lineage</topic><topic>Cells, Cultured</topic><topic>Coculture Techniques</topic><topic>Cyclic GMP - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Female</topic><topic>Immunomagnetic Separation</topic><topic>Male</topic><topic>Membrane Proteins - metabolism</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myocytes, Cardiac - drug effects</topic><topic>Myocytes, Cardiac - enzymology</topic><topic>Nitric Oxide - metabolism</topic><topic>Nitric Oxide Donors - pharmacology</topic><topic>Nitric Oxide Synthase Type III - genetics</topic><topic>Nitric Oxide Synthase Type III - metabolism</topic><topic>Paracrine Communication - drug effects</topic><topic>Sarcomeres - drug effects</topic><topic>Sarcomeres - enzymology</topic><topic>Signal Transduction</topic><topic>Soluble Guanylyl Cyclase - deficiency</topic><topic>Soluble Guanylyl Cyclase - genetics</topic><topic>Soluble Guanylyl Cyclase - metabolism</topic><topic>Time Factors</topic><topic>Transfection</topic><topic>Wnt Signaling Pathway - drug effects</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>De Pauw, Aurelia</creatorcontrib><creatorcontrib>Massion, Paul</creatorcontrib><creatorcontrib>Sekkali, Belaid</creatorcontrib><creatorcontrib>Andre, Emilie</creatorcontrib><creatorcontrib>Dubroca, Caroline</creatorcontrib><creatorcontrib>Kmecova, Jana</creatorcontrib><creatorcontrib>Bouzin, Caroline</creatorcontrib><creatorcontrib>Friart, Ann</creatorcontrib><creatorcontrib>Sibille, Catherine</creatorcontrib><creatorcontrib>Gilon, Patrick</creatorcontrib><creatorcontrib>De Mulder, Delphine</creatorcontrib><creatorcontrib>Esfahani, Hrag</creatorcontrib><creatorcontrib>Strapart, Adrien</creatorcontrib><creatorcontrib>Martherus, Ruben</creatorcontrib><creatorcontrib>Payen, Valéry</creatorcontrib><creatorcontrib>Sonveaux, Pierre</creatorcontrib><creatorcontrib>Brouckaert, Peter</creatorcontrib><creatorcontrib>Janssens, Stefan</creatorcontrib><creatorcontrib>Balligand, Jean-Luc</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cardiovascular research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>De Pauw, Aurelia</au><au>Massion, Paul</au><au>Sekkali, Belaid</au><au>Andre, Emilie</au><au>Dubroca, Caroline</au><au>Kmecova, Jana</au><au>Bouzin, Caroline</au><au>Friart, Ann</au><au>Sibille, Catherine</au><au>Gilon, Patrick</au><au>De Mulder, Delphine</au><au>Esfahani, Hrag</au><au>Strapart, Adrien</au><au>Martherus, Ruben</au><au>Payen, Valéry</au><au>Sonveaux, Pierre</au><au>Brouckaert, Peter</au><au>Janssens, Stefan</au><au>Balligand, Jean-Luc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>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</atitle><jtitle>Cardiovascular research</jtitle><addtitle>Cardiovasc Res</addtitle><date>2016-10</date><risdate>2016</risdate><volume>112</volume><issue>1</issue><spage>478</spage><epage>490</epage><pages>478-490</pages><issn>0008-6363</issn><eissn>1755-3245</eissn><abstract>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.
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.
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.</abstract><cop>England</cop><pmid>27520736</pmid><doi>10.1093/cvr/cvw196</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
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| ispartof | Cardiovascular research, 2016-10, Vol.112 (1), p.478-490 |
| issn | 0008-6363 1755-3245 |
| language | eng |
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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Oxford University Press Journals All Titles (1996-Current); Alma/SFX Local Collection |
| subjects | Adult Stem Cells - drug effects Adult Stem Cells - metabolism Animals Antigens, Ly - metabolism beta Catenin - genetics beta Catenin - metabolism Cell Differentiation - drug effects Cell Lineage Cells, Cultured Coculture Techniques Cyclic GMP - metabolism Dose-Response Relationship, Drug Female Immunomagnetic Separation Male Membrane Proteins - metabolism Mice, Inbred C57BL Mice, Knockout Myocytes, Cardiac - drug effects Myocytes, Cardiac - enzymology Nitric Oxide - metabolism Nitric Oxide Donors - pharmacology Nitric Oxide Synthase Type III - genetics Nitric Oxide Synthase Type III - metabolism Paracrine Communication - drug effects Sarcomeres - drug effects Sarcomeres - enzymology Signal Transduction Soluble Guanylyl Cyclase - deficiency Soluble Guanylyl Cyclase - genetics Soluble Guanylyl Cyclase - metabolism Time Factors Transfection Wnt Signaling Pathway - drug effects |
| title | 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 |
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