THE EFFECTS OF MYOCARDIAL INFARCTION ON NEUROINFLAMMATION: FOCUS ON THE ROLE OF EXTRACELLULAR VESICLES

Cardiovascular diseases (CVDs) are considered the leading cause of premature death globally, with an estimated 17 million deaths yearly, according to the World Health Organization (WHO). CVDs include a collection of diseases, most importantly cardiac ischemia. Complications following cardiac ischemia represent a significant risk factor that threatens the patient’s quality of life in both short and long terms and affect many body organs, such as the brain. Many research studies demonstrated a strong correlation between myocardial infarction (MI) and cerebrovascular diseases. For example, after MI, patients are highly susceptible to develop various cognitive and behavioral disorders, such as Alzheimer’s disease and dementia. The exact molecular mechanism underlying this relationship is poorly understood and still needs a lot of investigation. According to this, cardiologists and neurologists are highly interested in understanding the alterations that occur within the brain following MI. This dissertation focused on studying the effects of MI on the occurrence and evolution of the neuroinflammation, with a particular focus on the behavior of neuroglia. Additionally, it investigated potential alterations in blood brain barrier (BBB) integrity and the passage of cardiac extracellular vesicles (EVs) through it as a consequence of the ischemic event. Moreover, it highlighted the beneficial role of using the pharmacological treatment, montelukast, as a tool to counteract potential alterations at the cerebral level following MI. This dissertation project comprised two parts: in-vivo and in-vitro assessments. The in-vivo study involved the induction of MI in a mouse model to study the potential effects post-MI on the cerebral level using a set of cellular and molecular biology assays. Significant alterations in brain tight junction proteins, neuroinflammatory gene expression and circulating levels of microvesicles were observed during the acute phase after MI. The activation of microglial cells in terms of inflammatory signaling pathways was significantly upregulated in the sub-chronic phase. Moreover, the chronic phase showed an elevation in the number of oligodendrocyte precursor cells (OPCs), as well as the maturation and proliferative state of some of these OPCs, alongside the continuous activation of microglial/infiltrated macrophage cells. Of note, the results showed that pharmacological treatment using montelukast was in grade to counteract the observed alterations in BBB integrity and neuroinflammatory processes activation during the acute phase. The second part of this dissertation was carried out through an in-vitro assessment and aimed to shed the light on the potential involvement of the EVs released following the cardiac ischemic event in the changes observed in BBB integrity. Results revealed that conditioned medium and extracellular vesicles released from cardiac cells exposed to oxygen and glucose deprivation (OGD) were able to alter the level of tight junction protein occludin in brain microvascular endothelial cells, strongly suggesting the possible contribution of EVs released after cardiac ischemia in the activation of the neuroinflammatory processes observed in-vivo. Altogether, the results obtained in this dissertation represent a cornerstone and pave the way for novel future research to delve into the world of EVs and unravel their potential role in the activation of the neuroinflammatory processes after cardiac ischemia. Furthermore, they open avenues to explore the prospective use of these EVs as markers and in targeted drug therapy to improve cardiovascular disease prognosis and outcomes, as well as to protect against the subsequent undesired consequences at the cerebral level over time after MI.