THE IMPACT OF ESTROGEN DEFICIENCY ON CEREBRAL HOMEOSTASIS FOLLOWING ACUTE MYOCARDIAL INFARCTION IN FEMALE MICE

Abstract

Acute myocardial infarction (AMI) is marked by a decline in cardiac output (CO) and a subsequent reduction in cerebral blood flow (CBF). This hypoperfusion poses a risk of brain damage and may contribute to accelerated cognitive dysfunction and Alzheimer's disease (AD) in the context of aging. Estrogen, known for its role in neuromodulation and hippocampal synaptic plasticity, becomes deficient during menopause, coinciding with cognitive changes and brain pathologies. The primary objective of this study is to assess whether the early stages of myocardial infarction (MI) reveal potential signs of brain injury in the presence or absence of ovariectomy. Our study involved ovariectomized and non-ovariectomized female mice subjected to left anterior descending (LAD) coronary artery coronary artery ligation at five months of age. Hemodynamic analyses revealed a significant increase in left ventricular end diastolic volume (LVEDV) and left ventricular internal diameter end diastole (LVIDd), seven days after LAD ligation in the female MI (FMI) group only. However, both the FMI and female with ovariectomy followed by a myocardial infarction (FOVX-MI) groups, exhibited a notable increase in left ventricular end systolic volume (LVESV) and left ventricular internal diameter end systole (LVIDs) after seven days post-MI. Additionally, a substantial decrease in both ejection fraction (EF) and CO, in FMI and FOVX-MI groups was observed at D7. Cardiac dysfunction is evident in the FOVX-MI group, resulting in a notable reduction in CO, however, it is noteworthy that EF demonstrates a substantial decrease in the FOVX-MI group at D7 when compared to FMI group. Several key findings emerged, including mRNA-levels that revealed the absence of increased inflammatory markers’ expression (IL-1 β, IL-6, TNF- α, iNOS, and IL-4) in the brain hippocampus. Analysis of protein blots within the hippocampus indicated the absence of significant alterations in neurotrophic and growth factors (BDNF and bFGF). Notably, no signs of neuronal apoptosis were observed, as evidenced by the unchanged expression of caspase-3 protein, and the absence of expressed chromatolysis observed by Nissl stain. Furthermore, our molecular assessment uncovered a significant but comparable increase in the reactive oxygen species (ROS) post-MI in both groups. Despite these changes, hippocampal hypoxia, assessed through hypoxia-inducible factor-1 alpha (HIF-1α), remained unaltered. In summary, our study did not demonstrate significant acute cerebral injuries or the initiation of chronic adverse neurological outcomes in the brain hippocampus within 7 days post-MI. This suggests a relatively short timeframe for the potential detrimental effects of MI and estrogen deficiency on the hippocampus. Further research is warranted to explore longer timeframe post-MI and its impact on cerebral injury in the presence or absence of ovariectomy.