Baker, Andrew

Newby, David

Sluimer, Judith

Hung, John David

2021-06-17T16:08:29Z

2021-06-17T16:08:29Z

2021-07-31

Coronary heart disease is responsible for around 2 million deaths across Europe each year. This is largely caused by atherosclerosis, a chronic inflammatory disease of the vasculature characterized by development of plaque in the arterial wall. Advanced plaques may become unstable, carrying a risk of rupture or erosion and manifest as acute myocardial infarction. In patients with type 1 and type 2 myocardial infarction, mortality rates remain high; up to 15% and 25%, respectively. Although risk stratification tools like GRACE 2.0 score can robustly predict outcome in these patients, new therapies targeting the unstable plaque are still needed to address this global epidemic. Long noncoding RNAs (lncRNAs) are an emergent class of molecules with diverse functional roles, widely expressed in human physiology and disease. Although some lncRNAs have already been identified in cardiovascular disease, their potential as novel targets in the prevention of atherosclerosis remains unknown. The aim of this project was to discover important lncRNAs in unstable plaque and gain insight into their functional relevance. Analysis of RNA sequencing previously performed on stable and unstable atherosclerotic plaque identified a panel of 47 differentially regulated lncRNAs. I focused on LINC01272, a lncRNA upregulated in unstable plaque previously detected in inflammatory bowel disease, and ultimately renamed it PELATON (plaque enriched lncRNA in atherosclerotic and inflammatory bowel macrophage regulation). PELATON is highly monocyte- and macrophage-enriched across vascular cell types, and almost entirely nuclear by cellular fractionation (90%–98%). In situ hybridization confirmed enrichment of PELATON in areas of plaque inflammation, co-localising with macrophages around the shoulders and necrotic core of human plaque sections. Consistent with its nuclear localization, and despite containing a predicted open reading frame, PELATON did not demonstrate any protein-coding potential in vitro. Functionally, knockdown of PELATON significantly reduced phagocytosis, lipid uptake and reactive oxygen species production in high- content analysis, with a significant reduction in phagocytosis independently validated. Furthermore, CD36, a key mediator of phagocytic oxLDL (oxidized low-density lipoprotein) uptake was significantly reduced with PELATON knockdown. Taken together, these data demonstrate that a novel lncRNA (PELATON) is important to macrophage function in atherosclerotic plaque. Future work should focus on manipulation of PELATON, to potentially reduce plaque instability, and prevent cardiovascular events.

https://hdl.handle.net/1842/37702

http://dx.doi.org/10.7488/era/980

en

The University of Edinburgh

atherosclerosis

long non-coding RNA

Type 2 myocardial infarction

Role of long non-coding RNA in atherosclerosis

Thesis or Dissertation

Doctoral

PhD Doctor of Philosophy