Regulation of ROS production by succubate dehydrogenase in cardiac ischemia reperfusion

• Autores: Viteri Álvarez, Sonia Valeria
• Año de publicación: 2019
• Idioma: inglés
• Tipo de recurso: tesis de maestría
• Colaborador/a o director/a de tesis: Alvarez, Silvia; Bugger, Heiko; Donato, Martín; Mosca, Susana; Hannibal, Luciana
• Materia: Isquemia cardiaca; Especies de óxigeno reactivo; Reactive oxygen species; ROS; SIRT5; Cardiac ischemia reperfusion; Ciencias de la vida
• Institución: Universidad de Buenos Aires

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.\nWhile 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.\nRecent 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\nrequire 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
Magíster de la Universidad de Buenos Aires en Ciencias Biomédicas