Elucidating the Mechanisms Underlying the Rupture and Healing of Atherosclerotic Plaques and the Subsequent Identification of Novel Biomarkers and Therapeutic Targets

Abstract

Background
Atherosclerotic plaque rupture is the leading cause of myocardial infarction (MI) and stroke. This study aimed to understand how microRNA-mediated mechanisms contribute to the pathophysiology of plaque rupture and healing. I also aimed to identify the interaction between plaque-related microRNA and microglial cell activation associated with vascular dementia. I intended to demonstrate the validity of microRNAs as circulating biomarkers, together with opportunities for development of microRNA-based therapies.

Methods and Results
Next-generation sequencing (NGS) studies of stable and healed plaque rupture (HPR) plaques in human coronary arteries, and of monocyte/macrophage/foam cell pro-inflammatory signaling, identified 19 differentially expressed microRNA predicted to target a panel of proteins shown to be upregulated in macrophage dense shoulder regions following rupture. All 19 microRNAs were diOerentially expressed in microglia compared to monocytes/macrophages, with the expression pattern of miR-155-5p in CM suggestive of a modulatory network implicated in neuroinflammation via SIRT1. Based on our NGS findings, microRNA inhibition in a monocyte/macrophage cell line suggested that expression of miR-10b-5p and miR-142-3p is associated with regulation of the proatherogenic predicted protein target, XIAP. I identified downregulated circulating levels of miR-27b-5p and miR-142-3p in patients with clinically relevant atherosclerosis, including individuals selected for coronary artery bypass graft or following a major adverse cardiovascular event, compared to healthy controls.
Expression of circulating miR-34-5p in patients with clinical atherosclerosis was inversely correlated with the expression of anti-inflammatory mediators, IL-4 and IL-10. Spatial transcriptomic analysis of human stable and HPR plaques identified FTH1 as upregulated throughout a ruptured atherosclerotic vessel and downregulated in regions of healing in the plaque core.

Conclusion
These finding indicate the regulatory role of microRNAs in the pathogenesis of atherosclerosis and modulation of neuroinflammation, inferring their potential as biomarkers and therapeutic targets for the amelioration of plaque progression and potentiation of healing.

Date of Award	20 Jan 2026
Original language	English
Awarding Institution	University of Bristol
Supervisor	Jason L Johnson (Supervisor) & Thomas W Johnson (Supervisor)