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

James, Kreema LU orcid (2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
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... (More)
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.
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Please use this url to cite or link to this publication:
author
supervisor
opponent
  • MD, PhD Maegdefessel, Lars, Karolinska Institutet
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Cardiology, molecular biology, extracelluar vesicles, Micro-RNA, Protein
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2022:170
pages
67 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/67309288046
defense date
2022-12-15 08:30:00
ISSN
1652-8220
ISBN
978-91-8021-332-5
language
English
LU publication?
yes
id
304e60f0-0f1a-4310-aa92-0c53ec380bc0
date added to LUP
2022-11-16 11:10:44
date last changed
2022-11-29 10:44:41
@phdthesis{304e60f0-0f1a-4310-aa92-0c53ec380bc0,
  abstract     = {{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.<br/>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.<br/>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.<br/>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.<br/>}},
  author       = {{James, Kreema}},
  isbn         = {{978-91-8021-332-5}},
  issn         = {{1652-8220}},
  keywords     = {{Cardiology; molecular biology; extracelluar vesicles; Micro-RNA; Protein}},
  language     = {{eng}},
  number       = {{2022:170}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Micro-RNA: The “Micro”-managers of cardiovascular diseases - Role of extracellular vesicles-mediated miRNAs in cardiovascular diseases}},
  url          = {{https://lup.lub.lu.se/search/files/128692026/Thesis_Kreema_James_WEB.pdf}},
  year         = {{2022}},
}