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Identifier

000412732

Title

Role of oxidative stress and mitochondrial dysfunction in septic cardiomyopathy

Alternative Title

Ο ρόλος του οξειδωτικού στρές και της μιτοχονδριακής δυσλειτουργίας στη σηπτική καρδιομυοπάθεια

Author

Κοκκινάκη, Δήμητρα

Thesis advisor

Δροδάτος, Κωνσταντίνος

Reviewer

Καρδάσης, Δημήτριος
Τσατσάνης, Χρήστος

Abstract

Sepsis is a life-threatening condition and cardiovascular dysfunction frequently complicates sepsis, as its presence increases mortality rate from 20% to 90%. Various mechanisms have been implicated in the pathophysiology of septic cardiac dysfunction such as increased inflammation, oxidative stress, impaired β-adrenergic signaling, impaired metabolism and reduced ATP synthesis in cardiomyocytes. The underlying mechanisms, though, are not fully elucidated, which constitutes the reason for the lack of an effective treatment for septic cardiomyopathy. In our first study, we showed that in vivo inhibition of NOX2 by apocynin protects mice from sepsis-induced systolic dysfunction using both the LPS-injection model and the CLP model of polymicrobial sepsis. We showed that NOX2 inhibition preserved cardiac function, alleviated oxidative stress, reduced JNK activation and downregulation of metabolic genes without resolution of the inflammatory component of the disease, identifying a potentially novel role for NOX2 in the pathophysiology of the disease, acting through cardiac metabolism in a way that is largely independent of systemic inflammation. In the second study we performed, we used LGM2605, which is chemically synthesized SDG and we showed that the drug could successfully prevent the sepsis-induced cardiac dysfunction using the CLP model of polymicrobial sepsis. LGM2605 suppressed the sepsis-induced mitochondrial superoxide generation in vitro, restored the sepsis-induced impairment on mitochondrial number, increased the expression of MCU and increased the mitochondrial respiration levels as we observed by seahorse analysis. In both studies we showed the importance of anti-oxidant and metabolic therapies for treating septic cardiac dysfunction. Further studies are needed to support our hypothesis for targeting oxidative stress and mitochondrial dysfunction as a way to treat septic cardiomyopathy.

Language

English

Subject

Apocynin

LGM2605

NOX2

Σήψη

Issue date

2017-12-12

Collection

School/Department--School of Medicine--Department of Medicine--Post-graduate theses

Type of Work--Post-graduate theses