Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling

Programa de Doctorat en Medicina i Recerca Translacional

Detalles Bibliográficos
Autor: Guitart Mampel, Mariona
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:CBUC, CESCA
Repositorio:TDR. Tesis Doctorales en Red
OAI Identifier:oai:www.tdx.cat:10803/668102
Acceso en línea:http://hdl.handle.net/10803/668102
Access Level:acceso abierto
Palabra clave:Mitocondris
Mitocondrias
Mitochondria
Creixement fetal
Crecimiento fetal
Fetal growth
Metabolisme energètic
Metabolismo energético
Energy metabolism
Malalties del cor
Enfermedades del corazón
Heart diseases
Ciències de la Salut
616.1
id ES_37c0b0cb4d2de92ad0b65ef2c979b1f7
oai_identifier_str oai:www.tdx.cat:10803/668102
network_acronym_str ES
network_name_str España
repository_id_str
dc.title.none.fl_str_mv Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
title Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
spellingShingle Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
Guitart Mampel, Mariona
Mitocondris
Mitocondrias
Mitochondria
Creixement fetal
Crecimiento fetal
Fetal growth
Metabolisme energètic
Metabolismo energético
Energy metabolism
Malalties del cor
Enfermedades del corazón
Heart diseases
Ciències de la Salut
616.1
title_short Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
title_full Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
title_fullStr Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
title_full_unstemmed Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
title_sort Mitochondrial implication in intrauterine growth restriction and cardiovascular remodelling
dc.creator.none.fl_str_mv Guitart Mampel, Mariona
author Guitart Mampel, Mariona
author_facet Guitart Mampel, Mariona
author_role author
dc.contributor.none.fl_str_mv Cardellach, Francesc
Garrabou Tornos, Glòria
Facultat de Medicina i Ciències de la Salut
dc.subject.none.fl_str_mv Mitocondris
Mitocondrias
Mitochondria
Creixement fetal
Crecimiento fetal
Fetal growth
Metabolisme energètic
Metabolismo energético
Energy metabolism
Malalties del cor
Enfermedades del corazón
Heart diseases
Ciències de la Salut
616.1
topic Mitocondris
Mitocondrias
Mitochondria
Creixement fetal
Crecimiento fetal
Fetal growth
Metabolisme energètic
Metabolismo energético
Energy metabolism
Malalties del cor
Enfermedades del corazón
Heart diseases
Ciències de la Salut
616.1
description Programa de Doctorat en Medicina i Recerca Translacional
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/doctoralThesis
info:eu-repo/semantics/publishedVersion
format doctoralThesis
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10803/668102
url http://hdl.handle.net/10803/668102
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.rights.none.fl_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv http://creativecommons.org/licenses/by-nc-sa/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 149 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Universitat de Barcelona
publisher.none.fl_str_mv Universitat de Barcelona
dc.source.none.fl_str_mv TDX (Tesis Doctorals en Xarxa)
reponame:TDR. Tesis Doctorales en Red
instname:CBUC, CESCA
instname_str CBUC, CESCA
reponame_str TDR. Tesis Doctorales en Red
collection TDR. Tesis Doctorales en Red
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_ 1869406057347940352
spelling Mitochondrial implication in intrauterine growth restriction and cardiovascular remodellingGuitart Mampel, MarionaMitocondrisMitocondriasMitochondriaCreixement fetalCrecimiento fetalFetal growthMetabolisme energèticMetabolismo energéticoEnergy metabolismMalalties del corEnfermedades del corazónHeart diseasesCiències de la Salut616.1Programa de Doctorat en Medicina i Recerca TranslacionalIntrauterine growth restriction (IUGR) is an obstetric complication characterized by placental insufficiency and secondary cardiovascular remodeling that may lead to cardiomyopathy in adulthood. Its etiology and potential therapeutics are poorly understood. Mitochondrial bioenergetics pathways are mainly regulated by nuclear effectors such as sirtuins and are essential for embryonic development and cardiovascular function. Members of our group developed a rabbit model of IUGR and cardiovascular remodeling, in which heart, mitochondrial alterations were observed by microscopic and transcriptomic analysis. We aimed to evaluate if such alterations are translated at a functional mitochondrial level to establish the ethiopathology and potential therapeutic targets for this obstetric complication. For that aim, heart and placenta from the rabbit model was included as well as placenta from human pregnancies together with maternal and neonatal blood. At delivery, peripheral blood and cord blood mononuclear cells (PBMC and CBMC, respectively) were isolated. For the mitochondrial characterization, we assessed: oxygen consumption of the mitochondrial respiratory chain (MRC) by polarography using endogen cellular substrates and substrates for complex I. Also, enzymatic activity of complex I, II, IV, I+III and II+III of MRC, subunit protein expression of some of the MRC complexes (CII-SDHA, CII-SDHB and CIV-COX5A), Coenzyme Q levels, mitochondrial content (through citrate synthase activity, Tom20 expression or mitochondrial DNA (mtDNA) levels), oxidative stress (by lipid peroxidation and SOD2 activity) and ATP levels. Finally, Sirtuin 3 protein expression was measured by Western Blot. In the IUGR offspring from the rabbit model, we found a significant decrease of MRC function: enzymatic activity of complexes II, IV and II+III in IUGR hearts (p<0.05) and complexes II and II+III in IUGR placentas (p<0.05 and p<0.01, respectively). This was occurring with a not significant reduction in CI-stimulated oxygen consumption in both tissues and a significant decrease of complex II SDHB subunit expression in placenta (p<0.001). Additionally, levels of mitochondrial content, Coenzyme Q and cellular ATP were conserved. Lipid peroxidation significantly decreased in IUGR hearts (p<0.001), but not significantly increased in IUGR placentas. Finally, Sirtuin3 protein expression significantly increased in IUGR hearts (p<0.05). In human pregnancies, IUGR placental tissue showed an altered mitochondrial phenotype with a significant decrease of CI-stimulated oxygen consumption (p<0.05) and MRC complex I enzymatic activity (p<0.05). The enzymatic activities of the others MRC complexes and CS were preserved. In blood cells, conserved cellular oxygen consumption and trends to decrease CI-stimulated oxygen consumption was observed in maternal PBMC, but trends to decrease both cellular and CI-stimulated oxygen consumption were evidenced in neonatal CBMC, pointing out that IUGR newborns presented higher mitochondrial deficits compared to mothers. Moreover, no differences in MRC enzymatic activities in maternal PBMC or in neonatal CBMC were observed. Conserved CS activity was present in maternal PBMC but was significantly decreased in neonatal CBMC. So, in front of unaltered mtDNA levels in neonatal CBMC, alterations in neonatal CS would be related to Krebs cycle imbalances rather than to mitochondrial content. All these changes did not affect oxidative stress or ATP production in any tissue. Finally, Sirtuin3 protein expression also showed a relevant increase in human IUGR placenta (p=0.05). The relevance of this thesis relies on the description of mitochondrial impairment in the offspring of a rabbit model of IUGR but also in newborns from pregnancies complicated by IUGR. This mitochondrial imbalance is widely present in the different studied tissues, including the heart and the placenta from the rabbit model and the placenta and neonatal blood cells from human pregnancies. The mitochondrial characterization of this obstetric complication could help to greater understand the pathophysiologic mechanisms underlying cardiac remodelling and IUGR.Els nounats amb creixement intrauterí restringit (CIR) desenvolupen un remodelat cardiovascular fetal i idiopàtic que pot portar a cardiopatia durant l’etapa adulta. La bioenergètica mitocondrial, essencial pel desenvolupament embrionari i la funció cardíaca, està regulada per diferents proteïnes, entre elles la Sirtuina 3. Es tracta d’una proteïna deacetilasa d’alt interès terapèutic, ja que es pot modular a través de la dieta. Els cors de cries amb CIR d’un model animal de conill mostren alteracions transcriptòmiques i ultraestructurals a nivell mitocondrial. L’objectiu de l’estudi ha sigut determinar la implicació d’una possible disfunció mitocondrial i de la Sirtiuna 3 en el CIR. Les troballes demostren una alteració mitocondrial de la cadena respiratòria en el cor i la placenta de les cries amb CIR del model animal (sobretot a nivell de l’activitat enzimàtica dels complexes II i IV; p<0.05) i també a la placenta de gestants humanes amb CIR (especialment del complex I; p<0.05). A més a més, aquesta alteració mitocondrial s’ha evidenciat en els nounats amb CIR a través de la reducció de l’activitat de l’enzim citrat sintasa (p<0.05), suggerint alteracions a nivell del cicle de Krebs. L’ATP cel·lular i el dany oxidatiu es troba preservat en tots els teixits estudiats, excepte en el cor de les cries del model animal de CIR, on el trobem disminuït significativament (p<0.001). Aquest desajust mitocondrial va acompanyat d’un augment significatiu de l‘expressió de la proteïna Sirtuina 3 en el cor de les cries del model animal de CIR i també a la placenta de les gestants humanes amb CIR (p<0.05). Les troballes derivades d’aquest estudi permeten associar la disfunció mitocondrial al desenvolupament del CIR i el remodelat cardiovascular associat, donant lloc al disseny d’estratègies dietètiques destinades a modular l’esmentat desbalanç bioenergètic a través de la regulació de la Sirtuina 3.Universitat de BarcelonaCardellach, FrancescGarrabou Tornos, GlòriaFacultat de Medicina i Ciències de la Salut201920192018info:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersion149 p.application/pdfapplication/pdfhttp://hdl.handle.net/10803/668102TDX (Tesis Doctorals en Xarxa)reponame:TDR. Tesis Doctorales en Redinstname:CBUC, CESCAInglésL'accés als continguts d'aquesta tesi queda condicionat a l'acceptació de les condicions d'ús establertes per la següent llicència Creative Commons: http://creativecommons.org/licenses/by-nc-sa/4.0/http://creativecommons.org/licenses/by-nc-sa/4.0/info:eu-repo/semantics/openAccessoai:www.tdx.cat:10803/6681022026-06-14T12:46:07Z
score 15.301603

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