Targeting non-coding RNAs in unstable atherosclerotic plaques: Mechanism, regulation, possibilities, and limitations

Abstract

Cardiovascular diseases (CVDs) caused by arteriosclerosis are the leading cause of death and disability worldwide. In the late stages of atherosclerosis, the atherosclerotic plaque gradually expands in the blood vessels, resulting in vascular stenosis. When the unstable plaque ruptures and falls off, it blocks the vessel causing vascular thrombosis, leading to strokes, myocardial infarctions, and a series of other serious diseases that endanger people's lives. Therefore, regulating plaque stability is the main means used to address the high mortality associated with CVDs. The progression of the atherosclerotic plaque is a complex integration of vascular cell apoptosis, lipid metabolism disorders, inflammatory cell infiltration, vascular smooth muscle cell migration, and neovascular infiltration. More recently, emerging evidence has demonstrated that non-coding RNAs (ncRNAs) play a significant role in regulating the pathophysiological process of atherosclerotic plaque formation by affecting the biological functions of the vasculature and its associated cells. The purpose of this paper is to comprehensively review the regulatory mechanisms involved in the susceptibility of atherosclerotic plaque rupture, discuss the limitations of current approaches to treat plaque instability, and highlight the potential clinical value of ncRNAs as novel diagnostic biomarkers and potential therapeutic strategies to improve plaque stability and reduce the risk of major cardiovascular events.

Keywords: atherosclerotic plaques; non-coding RNAs; plaque instability; plaque rupture.

Figure 1

Non-coding nucleic acids participate the regulation of unstable plaques via mediating functions of endothelial cells, vascular smooth muscle cells and macrophages. As shown, there is a thin fibrous cap in the unstable plaque, and the vulnerable sites are rich in lipid cores, including a large number of apoptotic cells, cholesterol crystals, lipid-rich foam cells, and so on. Among them, in endothelial cells, miR-200C, miR-455-3p, miR-10b and miR-21 were significantly up-regulated, while miR-2b and LncRNA-UC.98 were down-regulated. miR-124-3p was increased and miR-133a, miR-145, miR-210, miR-21, miR-145 were significantly decreased in VSMCs. In addition, miR-23a-5p and miR-10b were up-regulated in macrophages, while miR-150, miR-196 and miR-24 were obviously down-regulated.

Figure 2

Regulatory mechanism of endothelial cells in unstable plaques. Inhibition of endothelial cell apoptosis induced by ox-LDL was mainly through WNT/JNK pathway after Dickkopf1 (DKK1) silencing. The combination of vascular endothelial growth factor receptor 2 (VEGFR2) and its ligand metalloprotease 10 (ADAM10) induces the phosphorylation of ERK1/2 through PLCγ/PI3K signal transduction and promotes the migration of ECs. Oxidative stress and hypoxia induce transforming growth factor-β (TGF-β) to stimulate the phosphorylation of SNAI2 and SMAD3, resulting in endothelial to mesenchymal transition (EndMT). P2Y2 receptor (P2Y2R) deletion can promote the expression of vascular adhesion molecule-1 (VCAM-1) and endothelial nitric oxide synthase (eNOS) in ECs, thus promote the activity of nitric oxide (NO) and matrix metalloproteinase-2 (MMP-2), then increase endothelial inflammation. Oleic acid suppresses cell apoptosis by inhibiting Toll-like receptor-activated JNK/NF-κB/IκBα pathway and the expression of TNF-α, MCP-1 and ICAM-1.

Figure 3

Regulatory mechanism of VSMC in unstable plaques. Serum response factor (SRF) blocks the inflammatory pathway by inhibiting ERK/JNK/C-Jun pathway and the expression of IL-1β, IL-6 and CCL2. ROS activates the phosphorylation of AMPK and induces phenotypic transformation of VSMCs through the klf4-dependent IκBα/NF-κB p65 pathway. Sirtuin6 (SIRT6) promotes the increase of IL-1β and IL-18 and induces VSMCs senescence by activating the phosphorylated p38/JNK/ERK1-Beat 2 pathway.

Figure 4

Regulatory mechanism of macrophages in unstable plaques. Insulin-like growth factor-1 receptor (IGF-1R) deletion inhibits cholesterol outflow by suppressing the expression of TNF-α, MCP-1 and IL-6 through ABCA1/ABCG1 pathway. In contrast, C1q/tumor necrosis factor-related protein-3 (CTRP3) promotes cholesterol outflow through PPAR-γ. The high expression of CTRP3 and CTRP9 can inhibit the macrophage inflammation through NFκB pathway. Pigment epithelium-derived factor (PEDF) can activate ERK, p38 and JNK phosphorylation to inhibit macrophage inflammation. NLRP3 inflammasomes induces inflammation by activating IL-1β and IL-18. Interferon-γ produced by Th1 T cells and natural killer (NK) cells activates the phosphorylation of JAK and STAT to promote inflammation. Leukotriene receptors (LTs-R) and its cofactor FLAP target FLAP/5-LO/Leukotriene pathway to inhibit inflammation. The tyrosine kinase inhibitor AG1296 suppresses inflammation by reducing the expression of MMP-2 and MMP-9 via PDGF/PDGFR pathway.