Extracellular vesicles and acute coronary syndrome: impact on Ischemia/Reperfusion injury

Acute Coronary Syndrome (ACS) describes a range of myocardial ischemic state and it is associated with substantial morbidity, mortality and places a large financial burden on every health care system across the world. Percutaneous Coronary Intervention (PCI) is the most appropriate approach to restore the coronary blood flow and improve the patients’ outcome. However, new strategies should be investigated in order to reduce myocardial Ischemia/Reperfusion (I/R) injury (IRI) and improve clinical outcomes. Although the role of Extracellular Vesicles (EV) released in an I/R setting is still controversial, they are considered as possible biomarkers and cardioprotective effectors. EV are membranous vesicles carrying a wide range of bioactive molecules, such as proteins, lipids, messenger RNA (mRNA) and microRNA (miRNA) and have been recently recognised as one of the most relevant mechanisms of cell-to-cell communication both at local and remote sites. In particular, they have been acknowledged to contribute to several cardiovascular pathophysiological processes including angiogenesis, coagulation, tissue repair and inflammation. EV derive from several cell types and their content, including miRNA, non-coding RNA and circular RNA are considered interesting biomarkers. Furthermore, EV released from cardiac progenitor cells, cardiosphere cells, mesenchymal stem cells and platelets have been investigated as potential therapeutic tools. Conversely, Endothelial Cells (EC)-derived EV play a controversial role, thereby further studies are required. It has been largely demonstrated that the EV cargo is influenced by the microenvironment in which cells are confined therefore, the effect of both naïve EC-derived EV (eEV-naïve) and eEV released in response to interleukin-3 (IL-3) (eEV-IL-3) has been evaluated in in-vitro and ex-vivo I/R models. It has been demonstrated that eEV-naïve exerted cardioprotective effects on the whole heart, compared to eEV-IL-3. Label-free mass spectrometry and gene ontology experiments were crucial to confirm that the IL-3 drives changes in the protein cargo. eEV-naïve were found enriched in proteins crucial for the cardioprotective and anti-apoptotic pathways, while eEV-IL-3 displayed higher expression of proteins related to the inflammatory response. These differences in the cargo lead to the impairment of the cardioprotective action. In order to improve the patients’ outcome, it has been investigated whether serum-derived EV, recovered from patients with ACS and subjected to Remote Ischemic Pre-Conditioning (RIPC) or sham procedures, may be a suitable therapeutic approach to prevent IRI during PCI. The evaluation of EV-naïve and EV-RIPC effects, both in-vitro and ex-vivo, allowed to demonstrate that EV-naïve drive cardio-protection via STAT-3 phosphorylation, while EV-RIPC lead to Erk-1/2 activation, and lack of cardioprotective action. PCI has been recognised as the most appropriate approach for ACS patients, but the study of its effect on the EV protein cargo gave some interesting results: both EV-naïve and EV-RIPC fail to protect the heart both in in-vitro and ex-vivo I/R models. The robustness of these data in favour of EV application and their reproducibility both in-vitro and ex-vivo should be encouraging to move towards clinical trials. Unfortunately, the relevance of EV as mediators of cardiac damage or recovery upon IRI is still unclear, so further studies will be necessary before starting clinical trials.