Cellular Phenotypic Transformation During Atherosclerosis: The Potential Role of miRNAs as Biomarkers

Abstract

Cellular phenotypic transformation is a key process that occurs during the development and progression of atherosclerosis. Within the arterial wall, endothelial cells, vascular smooth muscle cells, and macrophages undergo phenotypic changes that contribute to the pathogenesis of atherosclerosis. miRNAs have emerged as potential biomarkers for cellular phenotypic changes during atherosclerosis. Monitoring miR-155-5p, miR-210-3p, and miR-126-3p or 5p levels could provide valuable insights into disease progression, risk of complications, and response to therapeutic interventions. Moreover, miR-92a-3p's elevated levels in atherosclerotic plaques present opportunities for predicting disease progression and related complications. Baseline levels of miR-33a/b hold the potential for predicting responses to cholesterol-lowering therapies, such as statins, and the likelihood of dyslipidemia-related complications. Additionally, the assessment of miR-122-5p levels may offer insights into the efficacy of low-density-lipoprotein-lowering therapies. Understanding the specific miRNA-mediated regulatory mechanisms involved in cellular phenotypic transformations can provide valuable insights into the pathogenesis of atherosclerosis and potentially identify novel therapeutic targets.

Keywords: arterial plaque rupture; heart attack; microRNAs; plaque stability.

Figure 1

MicroRNA Biogenesis Pathway and main mechanism of action. MicroRNA (miRNA) genes are transcribed by RNA polymerase II (pol II), leading to pri-miRNAs (primary transcript). The «cropping» step is mediated by the Drosha–DGCR8 nuclear complex. The product of this nuclear processing step is a ~70-nucleotide (nt) pre-miRNA, which possesses a short stem plus a ~2-nucleotide 3′ overhang. This structure is recognized by the nuclear export factor exportin-5. Pre-miRNA constitutes a transport complex together with exportin-5 and its cofactor Ran (GTP form). Following export, the cytoplasmic RNase III Dicer participates in another processing step (‘dicing’) to produce miRNA duplexes. The duplex is separated, and usually, one strand is selected as the mature miRNA, whereas the other strand is degraded. However, both 3p and 5p ends of a specific stem-loop sequence (like miR-21-3p or 5p) can be produced in different cardiac cells or within the same cell, leading to potential clinical application [39]. The main mechanism of action is the binding of miRNAs to the 3′-untranslated region (UTR) of mRNA, referred to as seed pairing, the perfect or near perfect complementary match of nucleotides 2–8 of the mature miRNA. The illustration is adapted from Kim 2005 [40].

Figure 2

Main miRNAs involved in cellular phenotypic transformation with potential interest as biomarkers. The vulnerable plaque phenotype is at the crossroads between the regulation of miR-197-3p, miR-122-5p, 3p, and 5p forms of miR-21. The pri-mir-17-92 region is coding for six different miRNAs: miR-17, -18a, -19a, -20a, -19b, and -92a-3p. The mature form of miR-92a-3p is crucial in acquiring the atherosclerosis phenotype. The magenta color indicates that angiogenesis, apoptosis, or senescence is related to endothelial cell biology. Not presented in the figure, the miR-33a and b have been linked to cholesterol-lowering therapies. Signs (+) indicate miRNAs with proatherosclerotic function, while (−) indicates miRNAs with antiatherosclerotic function. The miR-33 gene family encompasses 2 forms in humans: one on chromosome 22 called miR-33a and one on chromosome 17 called 33b; both these non-coding genes produce 3p and 5p mature forms.