Evaluation of Non-Transcriptional Pathways of High Density Lipoprotein-Mediated Ischemic Post-Conditioning

• Grant number: 19/23819-1
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2020
• End date: May 31, 2022
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Andrei Carvalho Sposito
• Grantee: Isabella Bonilha de Oliveira
• Host Institution: Faculdade de Ciências Médicas (FCM). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 13/07607-8 - OCRC - Obesity and Comorbidities Research Center, AP.CEPID

Abstract

The occlusion of a coronary artery by a thrombus generated over a ruptured atherosclerotic plaque is the main cause of myocardial infarction. Although reperfusion is necessary to improve patients' recovery, it is paradoxically agent of ischemic injury. The mitochondrial permeability transition pore (MPT) plays a pivotal role in the ischemia-reperfusion injury (IRI). Therefore, the inhibition of its opening by the survivor activator factor enhancement pathway (SAFE) and the reperfusion injury salvage kinase pathway (RISK) is an important target of ischemic conditioning. Several studies have shown that the high-density lipoprotein (HDL) possibly upregulates those pathways, thus reducing myocardial infarct size. In fact, injecting HDL during the seven first minutes of reperfusion reduced final infarct size by 45%. In our study, we will administer HDL to ex vivo Langendorff models during the first 7min of reperfusion and test whether HDL activates SAFE and RISK pathway and modulates mitochondrial activity. This effect will be further studied by selective inhition of SAFE and RISK elements, thus allowing us to compreehendf the mechanism by which HDL modulates mitochondrial activity during reperfusion injury. Still, HDL components, such as clusterin, S1P and Apo AI, will be evaluated separately, using in vitro models of hypoxia/reoxigenation. The contribution of S1P to mitochondrial modulation will also be evaluated by selective inhibition of S1P receptors.