LncRNA-modulated autophagy in plaque cells: a new paradigm of gene regulation in atherosclerosis?

Abstract

The development of atherosclerosis is accompanied by the functional deterioration of plaque cells, which leads to the escalation of endothelial inflammation, abnormal vascular smooth muscle cell phenotype switching and the accumulation of lipid-laden macrophages within vascular walls. Autophagy, a highly conserved homeostatic mechanism, is critical for the delivery of cytoplasmic substrates to lysosomes for degradation. Moderate levels of autophagy prevent atherosclerosis by safeguarding plaque cells against apoptosis, preventing inflammation, and limiting the lipid burden, whereas excessive autophagy exacerbates cell damage and inflammation and thereby accelerates the formation of atherosclerotic plaques. Increasing lines of evidence suggest that long noncoding RNAs can be either beneficial or detrimental to atherosclerosis development by regulating the autophagy level. This review summarizes the research progress related to 1) the significant role of autophagy in atherosclerosis and 2) the effects of the lncRNA-mediated modulation of autophagy on the plaque cell fate, inflammation levels, proliferative capacity, and cholesterol metabolism and subsequently on atherogenesis.

Keywords: atherosclerosis; autophagy; long noncoding RNAs.

Figure 1

Role of moderate autophagy in atherosclerosis. The process of autophagy primarily involves the following steps: phagophore elongation, autophagosome formation, autophagosome-lysosome fusion, autolysosome formation, acidic hydrolase-mediated degradation of the autophagosome cargo and recycling of constituent macromolecules. In addition, moderate autophagy can inhibit atherosclerosis by protecting plaque cells (i.e., ECs, VSMCs, and macrophages) against apoptosis, inflammation, lipid accumulation, and abnormal phenotype switching. ECs, endothelial cells; VSMCs, vascular smooth muscle cells.

Figure 2

Classification of lncRNAs based on their genomic region. I, II: Sense lncRNAs and antisense lncRNAs are located on the same and opposite strands, respectively, and overlap with neighboring genes; III: intronic lncRNAs are transcribed entirely from the introns of protein-encoding genes; IV: intergenic lncRNAs lie within the genomic interval between two genes; V, VI: divergent/convergent lncRNAs are transcribed in the opposite/same direction as nearby protein-encoding genes; VII, VIII: promoter/enhancer-associated lncRNAs originate from the promoter/enhancer regions of protein-encoding genes; and IX: lncRNAs are situated upstream of the promoter.

Figure 3

Schematic diagram of the four mechanisms of action of lncRNAs. (I) As molecular signals, lncRNAs are involved in gene transcription in response to various stimuli; (II) as decoys, lncRNAs can repress gene transcription by titrating transcription factors; (III) as scaffolds, lncRNAs can recruit different proteins to target genes; and (IV) as guides, lncRNAs can localize particular ribonucleoprotein complexes to specific chromatin targets.