MicroRNAs as Therapeutic Targets and Clinical Biomarkers in Atherosclerosis

Abstract

Atherosclerotic cardiovascular disease remains the leading cause of morbidity and mortality worldwide. Atherosclerosis develops over several decades and is mediated by a complex interplay of cellular mechanisms that drive a chronic inflammatory milieu and cell-to-cell interactions between endothelial cells, smooth muscle cells and macrophages that promote plaque development and progression. While there has been significant therapeutic advancement, there remains a gap where novel therapeutic approaches can complement current therapies to provide a holistic approach for treating atherosclerosis to orchestrate the regulation of complex signalling networks across multiple cell types and different stages of disease progression. MicroRNAs (miRNAs) are emerging as important post-transcriptional regulators of a suite of molecular signalling pathways and pathophysiological cellular effects. Furthermore, circulating miRNAs have emerged as a new class of disease biomarkers to better inform clinical diagnosis and provide new avenues for personalised therapies. This review focusses on recent insights into the potential role of miRNAs both as therapeutic targets in the regulation of the most influential processes that govern atherosclerosis and as clinical biomarkers that may be reflective of disease severity, highlighting the potential theranostic (therapeutic and diagnostic) properties of miRNAs in the management of cardiovascular disease.

Keywords: angiogenesis; endothelial dysfunction; foam cell formation; inflammation; oxidative stress; plaque rupture; plaque stability; smooth muscle cells; vasa vasorum.

Figure 1

MiRNAs in cholesterol homeostasis and reverse cholesterol transport. In the liver, miRNAs target critical mediators involved in cholesterol biosynthesis, exerting positive/atheroprotective (blue) or negative/atherogenic (red) effects. miRNAs target cholesterol uptake into the liver by inhibiting expression of cholesterol transporters scavenger receptor BI (SR-BI) and low density lipoprotein receptor (LDLR). MiRNAs also have a significant impact in mediating cholesterol efflux capacity from the atherosclerotic plaque.

Figure 2

miRNAs in atherosclerotic plaque initiation and progression. Damage to the endothelial lining of lesion-prone areas of the arterial vasculature is one of the earliest events that contributes to the pathobiology of atherosclerosis, promoting a pro-inflammatory milieu and inducing an oxidative stress environment, which facilitates the recruitment of monocytes to the vessel wall via the increased expression of cell adhesion molecules (CAMs) including ICAM-1 and VCAM-1. Monocytes undergo trans-endothelial migration into the intima, where they undergo differentiation into macrophages and become activated under inflammatory and oxidative stress conditions. LDL diffuses into the intima and undergoes oxidative modification, and is likely to be taken up by the macrophages. Atherosclerotic lesion progression involves the proliferation and migration of smooth muscle cells (SMCs) into the intima. Positive/atheroprotective (blue) or negative/atherogenic (red) effects of miRNAs on the atherosclerotic processes are shown.

Figure 3

miRNA regulation of atherosclerotic plaque rupture. Rupture-prone vulnerable atherosclerotic plaques typically consist of high inflammatory cell content (foam cells) and a large necrotic core covered by a thin fibrous cap. These vulnerable plaques have an increased susceptibility to rupture, often culminating in catastrophic clinical manifestations of myocardial infarction or ischaemic stroke. While the pathophysiology of plaque rupture is not fully understood, it is well accepted that lesion vulnerability is more closely associated with plaque composition than size. Positive/atheroprotective (blue) or negative/atherogenic (red) effects of miRNAs on the atherosclerotic processes are shown.

Figure 4

Disruption of physiological vasa vasorum contributes to plaque formation. Factors such as diabetes, hypertension and hypercholesteraemia can lead to localised or systemic inflammation and hypoxia driving atherogenic conditions. Formation of adventitial vasa vasorum (VV) occurs in response to the metabolic demand of the outer and medial layers of an artery. Under hypoxic conditions, hypoxia-inducible factor (HIF)-1α and HIF-2α induce vascular endothelial growth factor (VEGF)A, a proangiogenic mediator. Hypoxic conditions also provide favourable conditions for fibroblast growth factor (FGF)2, promoting EC growth and stabilising VV. Additionally, inflammation triggers VV sprouting from the adventitia into the arterial lumen by inducing secretion of several angiogenic growth factors.

Figure 5

Role of miRNAs in regulation and self-renewal of embryonic stem cells and differentiation of stem/progenitor cells into endothelial and smooth muscle cell lineages. Multiple miRNAs are involved in regulating ESC differentiation into multipotent stem/progenitor cells, largely by targeting stemness factors. miR-21, miR-134, miR-145, miR-296 and miR-470 promote ESC differentiation by inhibiting transcription factors Nanog, Sox2, Oct4, c-Myc and Klf4. In contrast, the miR 290-295 cluster inhibits progression, termed embryonic stem cell-specific cell cycle-regulating miRNAs. Other key miRNAs promote cardiovascular lineage differentiation and regulate cell phenotype, including endothelial and smooth muscle cell commitment.