Banca de QUALIFICAÇÃO: PLÍNIO BEZERRA PALÁCIO

Uma banca de QUALIFICAÇÃO de DOUTORADO foi cadastrada pelo programa.
STUDENT : PLÍNIO BEZERRA PALÁCIO
DATE: 17/02/2025
TIME: 14:00
LOCAL: Google meet
TITLE:
MODULATION OF mitoKATP CHANNELS IN PRECONDITIONING MODELS: IMPLICATIONS FOR THE DEVELOPMENT OF NEW THERAPIES.


KEY WORDS:

mitoKATP. Mitochondria. Ischemia/reperfusion. Hypertrophy. Oxidative stress. Caloric restriction. 


PAGES: 100
BIG AREA: Ciências Biológicas
AREA: Bioquímica
SUMMARY:
Myocardial ischemia, caused by the interruption of blood flow to the heart, and the subsequent reperfusion injury (IRI) are major contributors to cardiovascular mortality and morbidity. IRI is characterized by a cascade of events, including the generation of reactive oxygen species (ROS), calcium imbalance, and mitochondrial dysfunction, which lead to cell death. However, ischemic preconditioning (IP), which involves brief episodes of ischemia and reperfusion, has been shown to protect the heart against subsequent IRI damage. The mitochondrial ATP-sensitive channel (mitoKATP) has been implicated as a key mediator in IP-induced cardioprotection. This thesis investigated the role of mitoKATP in cardiac ischemia-reperfusion injury and explored the modulation of this channel as a potential therapeutic strategy. The objectives of this study included evaluating the impact of mitoKATP modulation (by activation/inhibition) in hearts subjected to ischemia-reperfusion and preconditioning, with a particular focus on the role of the cyclohexylurea portion of glibenclamide (a mitoKATP inhibitor) and the mediation of these effects. Experiments were conducted on animal models (rats and mice) using techniques such as Langendorff heart perfusion, triphenyltetrazolium chloride (TTC) staining, mitochondrial isolation, mitochondrial swelling assays, mitochondrial respiration measurements, and molecular docking. The results demonstrated that the cyclohexylurea portion of glibenclamide is essential for the inhibition of mitoKATP and the subsequent abolition of the cardioprotective effects of preconditioning. A glibenclamide analog lacking the cyclohexylurea portion failed to block the cardioprotection induced by diazoxide (a mitoKATP activator). Furthermore, the studies revealed the competitive nature of the interaction between glibenclamide and diazoxide at the mitoKATP binding site. This thesis contributes to the understanding of the role of mitoKATP in cardiac ischemia-reperfusion injury and highlights the therapeutic potential of mitoKATP modulation. The results suggest that targeting the cyclohexylurea portion of glibenclamide may be a promising strategy for the development of new cardioprotective agents, as well as understanding the homeostasis of the activation balance between ATP/GTP nucleotide levels for channel modulation.


COMMITTEE MEMBERS:
Interno - FRANCISCO NASCIMENTO PEREIRA JUNIOR
Externo à Instituição - FRANCISCO RODRIGO DE LEMOS CALDAS
Presidente - HEBERTY DI TARSO FERNANDES FACUNDO
Externo à Instituição - HENRIQUE DOUGLAS MELO COUTINHO - URCA
Notícia cadastrada em: 12/02/2025 13:41
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