Abstract
Phenotypic switching of vascular smooth muscle cells from a contractile to a synthetic state is implicated in diverse vascular pathologies, including atherogenesis, plaque stabilization, and neointimal hyperplasia. However, very little is known about the role of long noncoding RNA (lncRNA) during this process. Here, we investigated a role for lncRNAs in vascular smooth muscle cell biology and pathology. Using RNA sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein vascular smooth muscle cells following stimulation with interleukin-1α and platelet-derived growth factor. We focused on a novel lncRNA (Ensembl: RP11-94A24.1), which we termed smooth muscle-induced lncRNA enhances replication (SMILR). Following stimulation, SMILR expression was increased in both the nucleus and cytoplasm, and was detected in conditioned media. Furthermore, knockdown of SMILR markedly reduced cell proliferation. Mechanistically, we noted that expression of genes proximal to SMILR was also altered by interleukin-1α/platelet-derived growth factor treatment, and HAS2 expression was reduced by SMILR knockdown. In human samples, we observed increased expression of SMILR in unstable atherosclerotic plaques and detected increased levels in plasma from patients with high plasma C-reactive protein. These results identify SMILR as a driver of vascular smooth muscle cell proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies.
Highlights
Vessel wall remodelling is an integral pathological process central to cardiovascular diseases including atherogenesis, plaque rupture and neointimal hyperplasia associated vein graft failure and in-stent restenosis 1, 2
Induction of inflammatory and cell cycle pathways by IL1Į and PDGF We sought to identify long non coding RNA (lncRNA) that are regulated during the induction of proliferative and inflammatory pathways in human saphenous vein derived smooth muscle cells (HSVSMC)
Identification of differentially expressed LncRNAs in HSVSMC treated with IL1Į and PDGF We assessed whether lncRNAs were dynamically regulated by growth factor and cytokine stimulation
Summary
Vessel wall remodelling is an integral pathological process central to cardiovascular diseases including atherogenesis, plaque rupture and neointimal hyperplasia associated vein graft failure and in-stent restenosis 1, 2. Following pathological or iatrogenic vascular injury, the release of cytokines and growth factors from VSMC, aggregated platelets and inflammatory cells on the damaged intimal surface, leads to “phenotypic switching" of VSMC and the adoption of a more synthetic, pro-proliferative and pro-migratory state 3. Phenotypic switching of vascular smooth muscle cells (VSMCs) from a contractile to a synthetic state is implicated in diverse vascular pathologies including atherogenesis, plaque stabilisation, and neointimal hyperplasia. Methods and Results—Using RNA-sequencing, we identified >300 lncRNAs whose expression was altered in human saphenous vein (HSV) VSMCs following stimulation with IL1Į and PDGF. Conclusions—These results identify SMILR as a driver of VSMC proliferation and suggest that modulation of SMILR may be a novel therapeutic strategy to reduce vascular pathologies
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