microCardio · Functional high-throughput analysis of the role of microRNAs in cardiac ischemia-reperfusion injury

Functional high-throughput analysis of the role of microRNAs in cardiac ischemia-reperfusion injury

Ischemia-reperfusion injury is a major cause of morbidity and mortality transversal to different clinical settings and pathologies, including a wide range of cardiovascular diseases including myocardial infarction and cerebral ischemic stroke, the main cause of death worldwide. Ischemia is characterised by insufficient supply of blood to tissues causing tissue oxygen deprivation. Importantly, damage by prolonged ischemia is further aggravated by reperfusion, leading to irreversible tissue damage. As consequence, cardiac cells at the site of injury die and a fibrotic scar, composed mainly of extracellular matrix, is formed. Cardiac fibrosis greatly affects cardiac function due to the loss of myocardial contractility, which can progress to heart failure and eventually cause death. Identifying and understanding the factors contributing to cardiac fibrosis is essential to counteract the irreversible damage and to potentially develop novel therapeutic approaches to intervene in myocardial infarction. Recent studies have shown that microRNAs control various aspects of heart disease, including ischemia-reperfusion injury and cardiac fibrosis. Although a few microRNAs have already been implicated in this process, a comprehensive analysis of the functional role of microRNAs in cardiac fibrosis and ischemia-reperfusion injury is still missing. The main goal of this project was to identify microRNAs which modulate cardiac fibrosis and characterise the molecular mechanisms underlying their function. Particular emphasis was put in studying how miRNAs modulate cardiac fibroblasts’ proliferation and differentiation, and extracellular matrix deposition. This was achieved through gain-of-function high-throughput screenings using genome-wide microRNA libraries in the presence or absence of a stimulus for extracellular matrix deposition. The identification and characterisation of the molecular targets of the selected microRNAs is underway and will entail a combination of computational and experimental approaches. This project used innovative experimental approaches to unravel a previously unappreciated network of microRNAs and microRNA targets critical to cardiac fibrosis, which may reveal novel opportunities for therapeutic intervention, with important clinical implications.

Data: CORDIS, © European Union