Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion

Myocardial infarction is a worldwide public health problem with a very poor prognosis1. The use of thrombolytic therapy or percutaneous coronary intervention have demonstrated a high effectiveness in reducing lesion size after myocardial infarction. This beneficial effect is largely due to the limit...

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Autor principal: Viteri Álvarez, Sonia Valeria
Otros Autores: Alvarez, Silvia
Formato: Tesis de maestría acceptedVersion
Lenguaje:Inglés
Publicado: Facultad de Farmacia y Bioquímica 2019
Materias:
Isquemia cardiaca
Especies de óxigeno reactivo
Reactive oxygen species
ROS
SIRT5
Cardiac ischemia reperfusion
Ciencias de la vida
Acceso en línea:http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5941
http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5941.dir/5941.PDF
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spelling I28-R145-HWA_59412022-04-19 Myocardial infarction is a worldwide public health problem with a very poor prognosis1. The use of thrombolytic therapy or percutaneous coronary intervention have demonstrated a high effectiveness in reducing lesion size after myocardial infarction. This beneficial effect is largely due to the limitation of myocardial ischemia. While ultimately limiting myocardial infarct size, restoration of blood flow also causes additional cardiac injury termed reperfusion injury 2. Both mechanisms of cardiac injury, i.e. ischemia and reperfusion, are summarized as ischemia-reperfusion (I/R) injury. Mechanisms proposed to contribute to I/R injury include impaired mitochondrial energetics, dysregulation of intracellular Ca2+ handling, rapid restoration of physiologic pH, inflammation, opening of the mitochondrial permeability transition pore (PTP), and reactive oxygen species (ROS) generation2. While ROS production during I/R is still incompletely understood, Chouchani et al.1 recently provided evidence for an important role of succinate-driven ROS generation. During ischemia, succinate seems to accumulate due to succinate dehydrogenase (SDH)-mediated reduction of fumarate to succinate. Upon reperfusion, SDH immediately oxidizes the accumulated succinate and, with complex III and IV at full capacity, drives reverse electron transport (RET) through mitochondrial complex I, resulting in superoxide formation which may even account for the major part of mitochondrial ROS generated during I/R1. Recent evidence implies a role for mitochondrial sirtuins in regulating mitochondrial ROS generation. Sirtuins (SIRTs) are NAD+-dependent deacylases that regulate target enzyme activity by removal of protein lysine modifications. Among a total of seven mammalian orthologs, sirtuin 5 (SIRT5) is primarily localized within mitochondria where it primarily modifies energy metabolic enzymes by desuccinylation, demalonylation and deglutarylation, including SDH.3 Recently, lack of SIRT5 in mice has been shown to impair the recovery of cardiac function following I/R, and it has been proposed that increased succinylation of SDH may lead to RET-mediated ROS production. Since this mechanism remains poorly elucidated, it is our superior objective to understand how SIRT5 regulates mitochondrial ROS production and I/R injury. Since such studies will require specific interventions such as mutation studies and pharmacological treatments in an appropriate model system, the specific aim of the current master thesis project was to establish a knockdown of SIRT5 in H9C2 cardiac myoblasts using RNA interference, as well as to establish an I/R protocol that may mimic the in vivo condition of I/R injury. Fil: Viteri Álvarez, Sonia Valeria. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Buenos Aires, Argentina Alvarez, Silvia Facultad de Farmacia y Bioquímica Bugger, Heiko Viteri Álvarez, Sonia Valeria 2019-03-26 application/pdf Donato, Martín Mosca, Susana Hannibal, Luciana Isquemia cardiaca Especies de óxigeno reactivo Reactive oxygen species ROS SIRT5 Cardiac ischemia reperfusion eng Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/2.5/ar/ Ciencias de la vida Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion info:eu-repo/semantics/masterThesis info:ar-repo/semantics/tesis de maestría info:eu-repo/semantics/acceptedVersion http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5941 http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5941.dir/5941.PDF
institution Universidad de Buenos Aires
institution_str I-28
repository_str R-145
collection Repositorio Digital de la Universidad de Buenos Aires (UBA)
language Inglés
orig_language_str_mv eng
topic Isquemia cardiaca
Especies de óxigeno reactivo
Reactive oxygen species
ROS
SIRT5
Cardiac ischemia reperfusion
Ciencias de la vida
spellingShingle Isquemia cardiaca
Especies de óxigeno reactivo
Reactive oxygen species
ROS
SIRT5
Cardiac ischemia reperfusion
Ciencias de la vida
Viteri Álvarez, Sonia Valeria
Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
topic_facet Isquemia cardiaca
Especies de óxigeno reactivo
Reactive oxygen species
ROS
SIRT5
Cardiac ischemia reperfusion
Ciencias de la vida
description Myocardial infarction is a worldwide public health problem with a very poor prognosis1. The use of thrombolytic therapy or percutaneous coronary intervention have demonstrated a high effectiveness in reducing lesion size after myocardial infarction. This beneficial effect is largely due to the limitation of myocardial ischemia. While ultimately limiting myocardial infarct size, restoration of blood flow also causes additional cardiac injury termed reperfusion injury 2. Both mechanisms of cardiac injury, i.e. ischemia and reperfusion, are summarized as ischemia-reperfusion (I/R) injury. Mechanisms proposed to contribute to I/R injury include impaired mitochondrial energetics, dysregulation of intracellular Ca2+ handling, rapid restoration of physiologic pH, inflammation, opening of the mitochondrial permeability transition pore (PTP), and reactive oxygen species (ROS) generation2. While ROS production during I/R is still incompletely understood, Chouchani et al.1 recently provided evidence for an important role of succinate-driven ROS generation. During ischemia, succinate seems to accumulate due to succinate dehydrogenase (SDH)-mediated reduction of fumarate to succinate. Upon reperfusion, SDH immediately oxidizes the accumulated succinate and, with complex III and IV at full capacity, drives reverse electron transport (RET) through mitochondrial complex I, resulting in superoxide formation which may even account for the major part of mitochondrial ROS generated during I/R1. Recent evidence implies a role for mitochondrial sirtuins in regulating mitochondrial ROS generation. Sirtuins (SIRTs) are NAD+-dependent deacylases that regulate target enzyme activity by removal of protein lysine modifications. Among a total of seven mammalian orthologs, sirtuin 5 (SIRT5) is primarily localized within mitochondria where it primarily modifies energy metabolic enzymes by desuccinylation, demalonylation and deglutarylation, including SDH.3 Recently, lack of SIRT5 in mice has been shown to impair the recovery of cardiac function following I/R, and it has been proposed that increased succinylation of SDH may lead to RET-mediated ROS production. Since this mechanism remains poorly elucidated, it is our superior objective to understand how SIRT5 regulates mitochondrial ROS production and I/R injury. Since such studies will require specific interventions such as mutation studies and pharmacological treatments in an appropriate model system, the specific aim of the current master thesis project was to establish a knockdown of SIRT5 in H9C2 cardiac myoblasts using RNA interference, as well as to establish an I/R protocol that may mimic the in vivo condition of I/R injury.
author2 Alvarez, Silvia
author_facet Alvarez, Silvia
Viteri Álvarez, Sonia Valeria
format Tesis de maestría
Tesis de maestría
acceptedVersion
author Viteri Álvarez, Sonia Valeria
author_sort Viteri Álvarez, Sonia Valeria
title Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
title_short Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
title_full Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
title_fullStr Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
title_full_unstemmed Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion
title_sort regulation of ros production by succubate dehydrogenase in cardiac ischemia reperfusion
publisher Facultad de Farmacia y Bioquímica
publishDate 2019
url http://repositoriouba.sisbi.uba.ar/gsdl/cgi-bin/library.cgi?a=d&c=afamaster&cl=CL1&d=HWA_5941
http://repositoriouba.sisbi.uba.ar/gsdl/collect/afamaster/index/assoc/HWA_5941.dir/5941.PDF
work_keys_str_mv AT viterialvarezsoniavaleria regulationofrosproductionbysuccubatedehydrogenaseincardiacischemiareperfusion
_version_ 1766017555330236416

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