Endothelial DANCR deficiency promotes atherosclerotic plaque instability by targeting ribosomal protein L22.
TL;DR
Endothelial DANCR deficiency promotes atherosclerotic plaque instability through activation of the RPL22/p53 pathway, suggesting DANCR as a potential protective factor and therapeutic target in atherosclerosis.
Abstract
INTRODUCTION Long noncoding RNAs (lncRNAs) are key regulators of vascular endothelial function. The lncRNA differentiation antagonizing non-protein coding RNA (DANCR) is implicated in cell proliferation and inflammatory responses; however, its specific role in atherosclerosis remains undefined.
Objective
To investigate the role of DANCR in modulating endothelial adhesive capacity and atherosclerotic plaque instability.
Methods
DANCR expression was profiled in vascular tissues and cell lines using RNA fluorescence in situ hybridization and real-time qPCR. Endothelial-specific DANCR-knockout mice were generated and injected with recombinant adeno-associated virus carrying murine PCSK9 to induce atherosclerosis. Chromatin isolation by RNA purification followed by sequencing was performed to identify potential targets of DANCR. Plasma DANCR level was measured in healthy subjects (n = 42) and in patients with mixed plaques detected by coronary computed tomography angiography (n = 30).
Results
DANCR expression was predominantly expressed in endothelial cells and was significantly lower by 43% in the endothelium of human carotid plaques than normal vessels. Endothelial-specific knockout of DANCR in mice led to a 78% increase in aortic plaque area and a 1.1-fold elevation in the plaque instability index, characterized by enlarged necrotic cores, elevated type III/I collagen ratio, and increased macrophage infiltration. The ribosomal protein L22 (RPL22) was identified to be a target of DANCR which repressed its transcriptional expression. Endothelial-specific knockdown of RPL22 reversed the plaque progression and instability induced by DANCR deficiency in vivo. In vitro, DANCR reduced endothelial adhesion capacity and the expression of ICAM1 and VCAM1 via inhibition of the RPL22/p53 pathway. Clinically, plasma DANCR level was lower in patients with mixed plaques compared with control subjects.
Conclusions
Endothelial DANCR deficiency promotes atherosclerotic plaque instability through activation of the RPL22/p53 pathway, suggesting DANCR as a potential protective factor and therapeutic target in atherosclerosis.