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Novel insights into sex-specific and oestrogen-dependent mechanisms in myocardial ischaemia/reperfusion injury

Periodic Reporting for period 1 - SEXOGENIRI (Novel insights into sex-specific and oestrogen-dependent mechanisms in myocardial ischaemia/reperfusion injury)

Reporting period: 2021-06-01 to 2024-05-31

Acute myocardial infarction (MI) accounts for millions of morbidity and mortality cases worldwide. While the underlying pathophysiology of cardiomyocyte dysfunction and death during MI-related ischaemia/reperfusion injury (IRI), which occurs due to the restoration of coronary blood flow after MI, is well established, the relevance of sex-based differences in this context is poorly understood. In this action, we aim at understanding the effect of biological sex in the induction of a novel form of cell death in the setting of IRI.

The overall aim of the proposed research is to study the role of biological sex in oxeiptosis during myocardial IRI. The main hypothesis is that there is a sex-based difference in the occurrence of oxeiptosis following IRI. It is further hypothesised that E2 plays a major role in this process, potentially involving the modulation of the components of mitochondrial fusion (Fig. 1). The specific aims are to:
1) assess and characterise oxeiptosis in male vs. female mice following IRI;
2) investigate the potential role of E2 in the induction of oxeiptosis in IRI;
3) assess the regulation of mitochondrial fusion proteins by E2 in oxeiptosis following IRI;
4) identify potential small-molecule candidates that can inhibit the occurrence of H2O2-induced oxeiptosis and preserve mitochondrial morphology and function;
5) assess the levels of selected candidates involved in oxeiptosis and mitochondrial fusion proteins in LV samples from adult male and female patients with ischaemic cardiomyopathy, thereby taking a translational approach.
As the project was terminated early, i.e. within the first six months, no major work could be completed towards any of the objectives of the project.

As part of the dissemination and communication strategy, the research fellow and the supervisor authored and published the following review article in an open access journal:

Beikoghli Kalkhoran S, Kararigas G. Oestrogenic Regulation of Mitochondrial Dynamics. Int J Mol Sci 2022;23(3):1118