PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions

Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiat...

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Autores: Zotes, Teresa M, Arias, Cristina, Fuster, Jose J., Spada, Roberto, Pérez-Yagüe, Sonia, Hirsch, Emilio, Wymann, Matthias, Carrera, Ana C, Andres, Vicente, Barber, Domingo F
Tipo de recurso: artículo
Fecha de publicación:2013
País:España
Institución:Instituto de Salud Carlos III (ISCIII)
Repositorio:Repisalud
Idioma:inglés
OAI Identifier:oai:repisalud.isciii.es:20.500.12105/7546
Acceso en línea:http://hdl.handle.net/20.500.12105/7546
Access Level:acceso abierto
Palabra clave:Animals
Apoptosis
Atherosclerosis
Class Ib Phosphatidylinositol 3-Kinase
Cyclic AMP
Macrophages
Mice
Mice, Knockout
Receptors, LDL
Cell Proliferation
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network_acronym_str ES
network_name_str España
repository_id_str
spelling PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesionsZotes, Teresa MArias, CristinaFuster, Jose J.Spada, RobertoPérez-Yagüe, SoniaHirsch, EmilioWymann, MatthiasCarrera, Ana CAndres, VicenteBarber, Domingo FAnimalsApoptosisAtherosclerosisClass Ib Phosphatidylinositol 3-KinaseCyclic AMPMacrophagesMiceMice, KnockoutReceptors, LDLCell ProliferationAtherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110γ in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110γ(+/-) and LDLR(-/-)p110γ(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110γ(+/-) and p110γ(-/-) mice. Lack of p110γ in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110γ(-/-) mice were smaller than in LDLR(-/-)p110γ(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110γ(-/-) mouse lesions. This proliferation defect was also observed in p110γ(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110γ(-/-) mice. Moreover, p110γ deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR(-/-) mice lacking p110γ. Nonetheless, p110γ deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.Public Library of Science (PLOS)Ministerio de Ciencia e Innovación (España)Instituto de Salud Carlos IIIComunidad de Madrid (España)20192019-05-0720132013-01-0120132013-01-01journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttp://hdl.handle.net/20.500.12105/7546reponame:Repisaludinstname:Instituto de Salud Carlos III (ISCIII)InglésengES SAF-2007-60498 Not availableES SAF-2008-00471 Not availableES SAF-2011-23639 Not availableES SAF-2010-16044 Not availableES BES-2009-016547 Not availableES RD08 0075ES RD06 0014open accesshttp://purl.org/coar/access_right/c_abf2Atribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:repisalud.isciii.es:20.500.12105/75462026-06-12T12:43:37Z
dc.title.none.fl_str_mv PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
title PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
spellingShingle PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
Zotes, Teresa M
Animals
Apoptosis
Atherosclerosis
Class Ib Phosphatidylinositol 3-Kinase
Cyclic AMP
Macrophages
Mice
Mice, Knockout
Receptors, LDL
Cell Proliferation
title_short PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
title_full PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
title_fullStr PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
title_full_unstemmed PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
title_sort PI3K p110γ deletion attenuates murine atherosclerosis by reducing macrophage proliferation but not polarization or apoptosis in lesions
dc.creator.none.fl_str_mv Zotes, Teresa M
Arias, Cristina
Fuster, Jose J.
Spada, Roberto
Pérez-Yagüe, Sonia
Hirsch, Emilio
Wymann, Matthias
Carrera, Ana C
Andres, Vicente
Barber, Domingo F
author Zotes, Teresa M
author_facet Zotes, Teresa M
Arias, Cristina
Fuster, Jose J.
Spada, Roberto
Pérez-Yagüe, Sonia
Hirsch, Emilio
Wymann, Matthias
Carrera, Ana C
Andres, Vicente
Barber, Domingo F
author_role author
author2 Arias, Cristina
Fuster, Jose J.
Spada, Roberto
Pérez-Yagüe, Sonia
Hirsch, Emilio
Wymann, Matthias
Carrera, Ana C
Andres, Vicente
Barber, Domingo F
author2_role author
author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Ministerio de Ciencia e Innovación (España)
Instituto de Salud Carlos III
Comunidad de Madrid (España)
dc.subject.none.fl_str_mv Animals
Apoptosis
Atherosclerosis
Class Ib Phosphatidylinositol 3-Kinase
Cyclic AMP
Macrophages
Mice
Mice, Knockout
Receptors, LDL
Cell Proliferation
topic Animals
Apoptosis
Atherosclerosis
Class Ib Phosphatidylinositol 3-Kinase
Cyclic AMP
Macrophages
Mice
Mice, Knockout
Receptors, LDL
Cell Proliferation
description Atherosclerosis is an inflammatory disease regulated by infiltrating monocytes and T cells, among other cell types. Macrophage recruitment to atherosclerotic lesions is controlled by monocyte infiltration into plaques. Once in the lesion, macrophage proliferation in situ, apoptosis, and differentiation to an inflammatory (M1) or anti-inflammatory phenotype (M2) are involved in progression to advanced atherosclerotic lesions. We studied the role of phosphoinositol-3-kinase (PI3K) p110γ in the regulation of in situ apoptosis, macrophage proliferation and polarization towards M1 or M2 phenotypes in atherosclerotic lesions. We analyzed atherosclerosis development in LDLR(-/-)p110γ(+/-) and LDLR(-/-)p110γ(-/-) mice, and performed expression and functional assays in tissues and primary cells from these and from p110γ(+/-) and p110γ(-/-) mice. Lack of p110γ in LDLR(-/-) mice reduces the atherosclerosis burden. Atherosclerotic lesions in fat-fed LDLR(-/-)p110γ(-/-) mice were smaller than in LDLR(-/-)p110γ(+/-) controls, which coincided with decreased macrophage proliferation in LDLR(-/-)p110γ(-/-) mouse lesions. This proliferation defect was also observed in p110γ(-/-) bone marrow-derived macrophages (BMM) stimulated with macrophage colony-stimulating factor (M-CSF), and was associated with higher intracellular cyclic adenosine monophosphate (cAMP) levels. In contrast, T cell proliferation was unaffected in LDLR(-/-)p110γ(-/-) mice. Moreover, p110γ deficiency did not affect macrophage polarization towards the M1 or M2 phenotypes or apoptosis in atherosclerotic plaques, or polarization in cultured BMM. Our results suggest that higher cAMP levels and the ensuing inhibition of macrophage proliferation contribute to atheroprotection in LDLR(-/-) mice lacking p110γ. Nonetheless, p110γ deletion does not appear to be involved in apoptosis, in macrophage polarization or in T cell proliferation.
publishDate 2013
dc.date.none.fl_str_mv 2013
2013-01-01
2013
2013-01-01
2019
2019-05-07
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv http://hdl.handle.net/20.500.12105/7546
url http://hdl.handle.net/20.500.12105/7546
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.relation.none.fl_str_mv ES SAF-2007-60498 Not available
ES SAF-2008-00471 Not available
ES SAF-2011-23639 Not available
ES SAF-2010-16044 Not available
ES BES-2009-016547 Not available
ES RD08 0075
ES RD06 0014
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Atribución 4.0 Internacional
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Public Library of Science (PLOS)
publisher.none.fl_str_mv Public Library of Science (PLOS)
dc.source.none.fl_str_mv reponame:Repisalud
instname:Instituto de Salud Carlos III (ISCIII)
instname_str Instituto de Salud Carlos III (ISCIII)
reponame_str Repisalud
collection Repisalud
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,811543

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