LincRNA-p21 Regulates Neointima Formation, Vascular Smooth Muscle Cell Proliferation, Apoptosis, and Atherosclerosis by Enhancing p53 Activity

Abstract

Background Long non-coding RNAs (lncRNAs) recently have been implicated in many biological processes and diseases. Atherosclerosis is a major risk factor for cardiovascular disease. However, the functional role of lncRNAs in atherosclerosis is largely unknown. Methods and Results We identified lincRNA-p21 as a key regulator of cell proliferation and apoptosis during atherosclerosis. The expression of lincRNA-p21 was dramatically down-regulated in atherosclerotic plaques of ApoE−/− mice, an animal model for atherosclerosis. Through loss- and gain-of function approaches, we showed that lincRNA-p21 represses cell proliferation and induces apoptosis in vascular smooth muscle cells (VSMCs) and mouse mononuclear macrophage cells in vitro. Moreover, we found that inhibition of lincRNA-p21 results in neointimal hyperplasia in vivo in a carotid artery injury model. Genome-wide analysis revealed that lincRNA-p21 inhibition dysregulated many p53 targets. Furthermore, lincRNA-p21, a transcriptional target of p53, feeds back to enhance p53 transcriptional activity, at least in part, via binding to mouse double minute 2 (MDM2), an E3 ubiquitin-protein ligase. The association of lincRNA-p21 and MDM2 releases MDM2 repression of p53, enabling p53 to interact with p300 and bind to the promoters/enhancers of its target genes. Finally, we show that lincRNA-p21 expression is decreased in coronary artery disease patients. Conclusions Our studies identify lincRNA-p21 as a novel regulator of cell proliferation and apoptosis and suggest that this lncRNA could serve as a therapeutic target to treat atherosclerosis and related cardiovascular disorders.

Long Noncoding RNAs in Atherosclerosis

“…Huarte et al found that lincRNA-p21, which was a p53-induced lncRNA and function as a component of the p53 pathway, could downregulate various p53 target genes by interacting with p53 repressive complex 59) . Wu et al 60) confirmed that lincRNA-p21 suppresses cell proliferation and induces apoptosis and more importantly, lincRNA-p21 knockdown results in obvious neointimal hyperplasia. They found that lincRNA-p21 enhances p53 activity by directly binding to mouse double minute 2 (MDM2), thus decreasing MDM2-mediated inhibition of p53 and facilitating p53 binding to p300 for acetylation.…”

Long Noncoding RNA-GAS5

“…10 Smooth muscle-expressed lncRNAs regulate vascular smooth muscle cell (VSMC) proliferation, migration, and phenotypic switching. 11,12 Hypertension is usually characterized by abnormal vascular tone, which is regulated by vascular smooth muscle-mediated vessel contraction and endothelium-dependent vessel vasodilation. 13,14 We speculated that lncRNAs might regulate vascular tone via affecting endothelial cell (EC) and VSMC function.…”

The Roles of the Long Non-Coding RNA Transcripts in Cardiovascular Diseases

“…In another study, it has been demonstrated that lincRNA-p21 suppresses cell proliferation, induces apoptosis, and leads to neointimal hyperplasia along with the knockdown of lincRNA-p21. LincRNA-p21 increases the p53 activity by directly binding to mouse double minute 2 (MDM2); therefore, MDM2-mediated inhibition of p53 decreases and the binding of p53 to p300 is facilitated (40). In another study investigating the role of lncRNAs in smooth muscle cells, angiotensin II has been shown to induce VSMC hyperproliferation and hypertrophy (41).…”