Micro-RNA: The “Micro”-managers of cardiovascular diseases - Role of extracellular vesicles-mediated miRNAs in cardiovascular diseases

Sammanfattning: Cardiovascular disease (CVD) is the leading cause of death globally, impacted by both extrinsic and intrinsic factors. The disease at the molecular level, however, is governed by inflammation and characterized by endothelial dysfunction. Over the last decade extracellular vesicles (EVs) have emerged as crucial mediators of intercellular communication especially under varied pathophysiological conditions including CVD.EVs are known to carry several molecules of biological significance such as proteins, ligands, micro-RNAs, receptors, etc. The studies in this thesis focused on the micro-RNA content of circulating EVs in relation to endothelial dysfunction and atherosclerosis measured by novel and reliable clinical parameters. We identified three significant miRNAs from the circulating EVs from three different cohorts. These single stranded non-coding RNAs function by silencing protein coding mRNAs.miR-224-5p was associated with coronary flow reserve and was identified as a biomarker for a sub-type of hepatic EVs that lead to inflammation by upregulating ICAM-1. While the miRNAs, miR-451a and miR-16-5p were had lower expression in patients with vulnerable plaques with a negative association to platelet EVs. Further investigations revealed that the significant downregulation of these miRNAs in the circulating EVs of the patients was associated with an increase in inflammation and several anti-inflammatory proteins including adhesion molecules. Similarly, the miR-451a demonstrated its significance in an exploratory study involving EVs from ruptured coronary plaques and was observed to be associated to apoptosis related proteins along with adhesion molecules.The studies shed a light on the uptake of EVs and EV miRNA by recipient cells in the circulation especially the first barrier of endothelial cells and its effect on downstream translation. The studies also highlight the importance of micro-RNAs in the circulation as as prognostic and diagnostic biomarkers of CVD.