# Long non‐coding RNA lncAPAT promotes atherosclerotic plaque instability by targeting ribosomal protein L22

## TL;DR

A new long non-coding RNA called lncAPAT increases heart plaque instability by affecting macrophage inflammation and gene regulation.

## Contribution

Discovery of a novel human-specific lncRNA, lncAPAT, and its role in promoting atherosclerotic plaque instability via RPL22 inhibition.

## Key findings

- LncAPAT is highly expressed in patients with coronary artery disease and mixed plaques.
- LncAPAT promotes macrophage inflammation and plaque instability by inhibiting RPL22 transcription.
- RPL22 inhibition increases inflammatory cytokines and contributes to atherosclerosis progression.

## Abstract

Long non‐coding RNAs (lncRNAs) regulate macrophage inflammation and atherosclerotic plaque stability, but mechanisms need comprehensive investigations.

Whole‐transcriptome sequencing was used to identify a novel human‐specific lncRNA, lncAPAT (atherosclerotic plaque instability‐associated transcript), in the peripheral blood of patients with coronary artery disease (CAD; n = 5) with mixed plaques on coronary computed tomography angiography (CCTA). LncAPAT was quantified using quantitative real‐time polymerase chain reaction in the discovery cohort and independently validated in patients with coronary mixed plaques by CCTA (n = 22) and in patients with acute ST‐segment elevation myocardial infarction (STEMI; n = 22). Myeloid cell‐specific lncAPAT knock‐in mice were generated and injected with recombinant adeno‐associated virus of murine proprotein convertase subtilisin/kexin type 9 to induce atherosclerosis and explore the effects of lncAPAT on inflammation and plaque instability. Macrophages were cultured to evaluate lncAPAT function in vitro. Chromatin isolation by RNA purification and sequencing and RNA immunoprecipitation assays were used to identify potential targets of lncAPAT.

LncAPAT expression was highly expressed in the peripheral blood of CAD and STEMI patients compared with the control individuals. Mice with myeloid cell‐specific lncAPAT knock‐in showed an increased plaque burden (2.7‐fold), elevated macrophage counts (2.4‐fold), and higher matrix metalloproteinase (MMP) expression (3.3‐fold for MMP9, 2.0‐fold for MMP2) in thoracic aortic plaques. In vitro, lncAPAT significantly promoted the inflammatory responses, adhesive capacity and cholesterol accumulation of macrophages, and decreased the cholesterol efflux ratio. LncAPAT interacted with the promoter of the ribosomal protein L22 gene (RPL22) and inhibited RPL22 transcription. RPL22 inhibition significantly increased the expression of inflammatory cytokines. The RPL22 protein directly interacted with monocyte chemoattractant protein‐1 (MCP‐1) mRNA and decreased MCP‐1 expression. Furthermore, RPL22 expression in the peripheral blood was lower in CAD and STEMI patients than in control individuals.

LncAPAT promoted the macrophage inflammatory response by inhibiting RPL22 transcriptional activity, contributing to plaque instability.

A novel human‐specific long non‐coding RNA (lncRNA), named as lncAPAT, is highly expressed in the peripheral blood of patients with coronary mixed plaques.
LncAPAT increases thoracic aortic plaque instability and promotes macrophage inflammatory responses.
LncAPAT directly interacted with the promoter region of RPL22 to inhibit RPL22 transcriptional activity and increase the expression of MCP‐1, thereby contributing to plaque instability.

A novel human‐specific long non‐coding RNA (lncRNA), named as lncAPAT, is highly expressed in the peripheral blood of patients with coronary mixed plaques.

LncAPAT increases thoracic aortic plaque instability and promotes macrophage inflammatory responses.

LncAPAT directly interacted with the promoter region of RPL22 to inhibit RPL22 transcriptional activity and increase the expression of MCP‐1, thereby contributing to plaque instability.

LncAPAT interacted with the promoter region of RPL22 to inhibit RPL22 transcriptional activity and increase the expression of MCP‐1, thereby contributing to plaque instability.