Long Non-Coding RNAs Might Regulate Phenotypic Switch of Vascular Smooth Muscle Cells Acting as ceRNA: Implications for In-Stent Restenosis

Abstract

Coronary in-stent restenosis is a late complication of angioplasty. It is a multifactorial process that involves vascular smooth muscle cells (VSMCs), endothelial cells, and inflammatory and genetic factors. In this study, the transcriptomic landscape of VSMCs’ phenotypic switch process was assessed under stimuli resembling stent injury. Co-cultured contractile VSMCs and endothelial cells were exposed to a bare metal stent and platelet-derived growth factor (PDGF-BB) 20 ng/mL. Migratory capacity (wound healing assay), proliferative capacity, and cell cycle analysis of the VSMCs were performed. RNAseq analysis of contractile vs. proliferative VSMCs was performed. Gene differential expression (DE), identification of new long non-coding RNA candidates (lncRNAs), gene ontology (GO), and pathway enrichment (KEGG) were analyzed. A competing endogenous RNA network was constructed, and significant lncRNA–miRNA–mRNA axes were selected. VSMCs exposed to “stent injury” conditions showed morphologic changes, with proliferative and migratory capacities progressing from G0-G1 cell cycle phase to S and G2-M. RNAseq analysis showed DE of 1099, 509 and 64 differentially expressed mRNAs, lncRNAs, and miRNAs, respectively. GO analysis of DE genes showed significant enrichment in collagen and extracellular matrix organization, regulation of smooth muscle cell proliferation, and collagen biosynthetic process. The main upregulated nodes in the lncRNA-mediated ceRNA network were PVT1 and HIF1-AS2, with downregulation of ACTA2-AS1 and MIR663AHG. The PVT1 ceRNA axis appears to be an attractive target for in-stent restenosis diagnosis and treatment.

Transcriptomics analysis of long non-coding RNAs in smooth muscle cells from patients with peripheral artery disease and diabetes mellitus

“…The significantly differentially expressed lncRNA ACTA2-AS1 has been described so far, mainly in the context of cancer development 26 – 28 . However, Arencibia et al found that the ACTA2-AS1 might also regulate the phenotypic switch and proliferation of SMCs 29 . In addition, the downregulation of ACTA2-AS1 shows significant enrichment in collagen biosynthesis and alternation in the structure and composition of the extracellular matrix (ECM).…”

The synergistic effect of CDKN2B-AS1 and SPC25 on triple-negative breast cancer

“…Recently, studies have revealed that lncRNAs are aberrantly expressed in breast cancer and closely associated with the development and progression of breast cancer (20). LncRNAs can regulate mRNA expression through multiple mechanisms: epigenetic regulation, transcriptional regulation, post-transcriptional regulation, acting as ceRNA and other molecules mechanisms (21). However, the specific mechanism is still unclear and it is a challenge to use lncRNAs as biomarkers for diagnosis or therapeutic targets.…”

Global trends and Frontier topics about vascular smooth muscle cells phenotype switch: A bibliometric analysis from 1999 to 2021

“…Wang et al reported that Hsa_circ_0031608 might be involved in the rupture of intracranial aneurysm via regulating VSMCPS ( Wang et al, 2022 ). Arencibia et al showed that lncRNAs regulate VSMCPS and participate in the pathological process of in-stent stenosis ( Arencibia et al, 2022 ). Additionally, He et al showed that circChordc1 could suppress vascular remodeling and reverse pathological aortic aneurysm progression through optimized VSMCPS and improved their growth ( He et al, 2022 ).…”