Periodontitis has been associated with an increased risk of atherosclerosis, potentially through altered systemic monocyte and macrophage function. We aimed to identify a differentially expressed protein in naïve monocytes from individuals with periodontitis compared to controls and investigate its association with pro-atherosclerotic monocyte and macrophage functions. Peripheral blood monocytes were isolated from individuals with periodontitis and matched controls. Proteomic analysis and bioinformatics identified insulin-like growth factor-binding protein-6 (IGFBP-6) as a protein of interest. IGFBP-6 protein was quantified in monocytes, macrophages, foam cells, and plasma using Western blotting. To model periodontitis in vitro, monocytes and macrophages were treated with Porphyromonas gingivalis lipopolysaccharide. Extracellular vesicles were analysed for IGFBP-6 content and activity. Foam cell formation, cholesterol transporter expression, monocyte adhesion, macrophage transmigration, inflammatory cytokine production, and apoptosis were quantified. IGFBP-6 levels were reduced intracellularly but elevated in plasma in periodontitis, and similar patterns were observed in lipopolysaccharide-treated cells. IGFBP-6 in extracellular vesicles lacked biological activity. Reduced IGFBP-6 protein was associated with increased foam cell formation and downregulation of ATP-binding cassette subfamily-G1 (ABCG1), independent of IGF signalling. Restoration of IGFBP-6 was associated with reduced foam cell formation and inflammation, alongside inhibition of macrophage transmigration. These findings suggest that altered IGFBP-6 levels may contribute to the progression of atherosclerosis in periodontitis.

Small vascular graft engineering may help reduce early vein graft failure. We assessed the feasibility, safety, and in vivo vascular regeneration potential of the decellularised human saphenous vein (D-hSV) with and without pre-seeding with porcine endothelial-like cells (ELCs) following grafting in porcine carotid artery (CA). A total of 14 pigs received CA grafting of control D-hSVs (n = 7) or D-hSVs seeded with ELCs (SD-hSV; n = 7). Ultrasound vascular Doppler was undertaken before and after grafting, and at 4 weeks. Outcome measures included patency, intimal thickening (IT), in situ vascular regeneration, endothelial cell (EC) coverage, neo-angiogenesis, mesenchymal-EC transition, and contractile cells. All animals reached the predefined culling point in good health, with no feasibility/safety concerns. Mild graft dilatation occurred at 4 weeks vs. baseline, with no difference between groups. In total, 9/14 grafts (64.3%) remained patent at 4 weeks (4/7 (57.1%) vs. 5/7 (71.4%) in the D-hSV and SD-hSV groups, respectively). IT increased from 17.1 ± 4.7% at baseline to 54.1 ± 12.2% at 4 weeks. Vascular regeneration occurred in all patent grafts with EC coverage, an increase in collagen and elastin, vimentin, SM-MHC-11, and calponin, with no difference between groups. The D-hSV for arterial vascular grafting is feasible and safe and associated with signs of in situ vascular regeneration by host cells at 4 weeks. Pre-seeding with ELCs did not add benefits.

Outward remodelling of arteries is a feature of cardiovascular pathologies such as atherosclerosis and aneurysm, so a greater understanding of the processes involved in remodelling may aid the development of improved therapies for patients. As ageing increases the risk of atherosclerosis and aneurysmal disease, it was therefore hypothesised that ageing affects arterial remodelling and thereby contributes to these diseases. To test this hypothesis, we compared right carotid artery remodelling in young (2 months, n = 13) and old (18–20 months, n = 13) mice resulting from increased blood flow after ligation of the left carotid artery. The media area, thickness, collagen content and α-SM-actin content per cell of control right carotid arteries from old mice were significantly greater than observed in young mice. Positive remodelling was observed in the carotid arteries of both old and young mice 21 days after ligation of the left carotid artery. However, arteries from old mice had a significantly larger increase in lumen size and reduction in media area, thickness and α-SM-actin content per cell compared to young arteries, indicative of augmented positive remodelling in arteries from old mice. Remodelling was associated with significantly increased MMP-2 protein in arteries from young mice, but this was not observed in arteries from old mice. This study demonstrates that the extent of positive remodelling of carotid arteries is greater in old mice than in young mice and results in a potentially less resilient medial layer with decreased α-SM-actin content per cell, elastin and collagen that may promote atherosclerosis and aneurysm formation.

Abstract Funding Acknowledgements Type of funding sources: Other. Main funding source(s): British Heart Foundation Rationale The sudden exposure of venous endothelial cells (vECs) to arterial fluid shear stress (FSS) is thought to be a major contributor to coronary artery bypass vein graft failure (VGF). However, the acute effects of arterial FSS on the vEC secretome and the corresponding effects on underlying vascular smooth muscle cells (VSMCs) remains poorly characterised. Methods & Results Human umbilical vein endothelial cells (HUVECs; n=6) pre-conditioned to venous FSS (18h; 1.5 dynes/cm2) were further exposed to venous or arterial FSS (24h; 15 dynes/cm2) using an Ibidi pump system. Analysis of the EC secretome using Tandem Mass Tagging proteomics detected significantly increased fibroleukin (FGL2) in conditioned media from ECs exposed to arterial FSS compared to venous FSS (fold-change 1.97±0.72; P=0.0078). In addition, RT-qPCR analysis of FGL2 production showed a significant increase in vECs exposed to arterial FSS (2.11±0.27 vs. 0.05±0.04 log(copy number/mg); P=0.0312). Subsequently, pooled human saphenous vein VSMCs (3 donors per pool) were treated with conditioned media from ECs exposed to arterial FSS (n=6) which showed a significant increase in apoptosis, measured by active cleaved caspase-3 (CC3) immunocytochemistry (27±1% vs 22±1%; P=0.0391), and a significant decrease in the contractile markers smoothelin and desmin quantified by Western blotting (fold-change 0.76±0.06 and 0.44±0.11; P=0.004 and P=0.0421, respectively), in comparison to VSMCs treated with conditioned media from ECs exposed to venous FSS. Treatment of VSMCs (n=6) with recombinant FGL2 (20 ng/mL) for 72h likewise resulted in increased apoptosis (27±4% vs. 16±3%; P=0.0169) and decreased desmin and smoothelin (fold-change 0.68±0.03 and 0.61±0.07; P=0.0322 and P=0.0479, respectively). Conclusions The exposure of vECs to arterial FSS results in increased production and release of FGL2 which induced VSMC apoptosis and de-differentiation and therefore potentially contributes to VGF. Consequently, targeting FGL2 production or release may provide a therapeutic target to improve vein graft patency.

Adenoviruses (Ads) have demonstrated significant success as replication-deficient (RD) viral vectored vaccines, as well as broad potential across gene therapy and cancer therapy. Ad vectors transduce human cells via direct interactions between the viral fiber knob and cell surface receptors, with secondary cellular integrin interactions. Ad receptor usage is diverse across the extensive phylogeny. Commonly studied human Ad serotype 5 (Ad5), and chimpanzee Ad-derived vector “ChAdOx1” in licensed ChAdOx1 nCoV-19 vaccine, both form primary interactions with the coxsackie and adenovirus receptor (CAR), which is expressed on human epithelial cells and erythrocytes. CAR usage is suboptimal for targeted gene delivery to cells with low/negative CAR expression, including human dendritic cells (DCs) and vascular smooth muscle cells (VSMCs). We evaluated the performance of an RD Ad5 vector pseudotyped with the fiber knob of human Ad serotype 49, termed Ad5/49K vector. Ad5/49K demonstrated superior transduction of murine and human DCs over Ad5, which translated into significantly increased T cell immunogenicity when evaluated in a mouse cancer vaccine model using 5T4 tumor-associated antigen. Additionally, Ad5/49K exhibited enhanced transduction of primary human VSMCs. These data highlight the potential of Ad5/49K vector for both vascular gene therapy applications and as a potent vaccine vector.

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe−/− mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe−/− mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.

Hypertension induces cardiac fibrotic remodelling characterised by the phenotypic switching of cardiac fibroblasts (CFs) and collagen deposition. We tested the hypothesis that Wnt1-inducible signalling pathway protein-1 (WISP-1) promotes CFs’ phenotypic switch, type I collagen synthesis, and in vivo fibrotic remodelling. The treatment of human CFs (HCFs, n = 16) with WISP-1 (500 ng/mL) induced a phenotypic switch (α-smooth muscle actin-positive) and type I procollagen cleavage to an intermediate form of collagen (pC-collagen) in conditioned media after 24h, facilitating collagen maturation. WISP-1-induced collagen processing was mediated by Akt phosphorylation via integrin β1, and disintegrin and metalloproteinase with thrombospondin motifs 2 (ADAMTS-2). WISP-1 wild-type (WISP-1+/+) mice and WISP-1 knockout (WISP-1−/−) mice (n = 5–7) were subcutaneously infused with angiotensin II (AngII, 1000 ng/kg/min) for 28 days. Immunohistochemistry revealed the deletion of WISP-1 attenuated type I collagen deposition in the coronary artery perivascular area compared to WISP-1+/+ mice after a 28-day AngII infusion, and therefore, the deletion of WISP-1 attenuated AngII-induced cardiac fibrosis in vivo. Collectively, our findings demonstrated WISP-1 is a critical mediator in cardiac fibrotic remodelling, by promoting CFs’ activation via the integrin β1-Akt signalling pathway, and induced collagen processing and maturation via ADAMTS-2. Thereby, the modulation of WISP-1 levels could provide potential therapeutic targets in clinical treatment.

Background and aims CCN4/WISP-1 regulates various cell behaviours that contribute to atherosclerosis progression, including cell adhesion, migration, proliferation and survival. We therefore hypothesised that CCN4 regulates the development and progression of atherosclerotic plaques. Methods We used a high fat fed ApoE-/- mouse model to study atherosclerotic plaque progression in the brachiocephalic artery and aortic root. In protocol 1 male ApoE-/- mice with established plaques were given a CCN4 helper-dependent adenovirus to see the effect of treatment with CCN4, while in protocol 2 male CCN4-/- ApoE-/- were compared to CCN4+/+ApoE-/- mice to assess the effect of CCN4 deletion on plaque progression. Results CCN4 overexpression resulted in reduced occlusion of the brachiocephalic artery with less apoptosis, fewer macrophages, and attenuated lipid core size. The amount of plaque found on the aortic root was also reduced. CCN4 deficiency resulted in increased apoptosis and occlusion of the brachiocephalic artery as well as increased plaque in the aortic root. Additionally, in vitro cells from CCN4-/- ApoE-/- mice had higher apoptotic levels. CCN4 deficiency did not significantly affect blood cholesterol levels or circulating myeloid cell populations. Conclusions We conclude that in an atherosclerosis model the most important action of CCN4 is the effect on cell apoptosis. CCN4 provides pro-survival signals and leads to reduced cell death, lower macrophage number, smaller lipid core size and reduced atherosclerotic plaque burden. As such the pro-survival effect of CCN4 is worthy of further investigation, in a bid to find a therapeutic for atherosclerosis.

The sudden exposure of venous endothelial cells (vECs) to arterial fluid shear stress (FSS) is thought to be a major contributor to coronary artery bypass vein graft failure (VGF). However, the effects of arterial FSS on the vEC secretome are poorly characterised. We propose that analysis of the vEC secretome may reveal potential therapeutic approaches to suppress VGF. Human umbilical vein endothelial cells (HUVECs) pre-conditioned to venous FSS (18 h; 1.5 dynes/cm2) were exposed to venous or arterial FSS (15 dynes/cm2) for 24 h. Tandem Mass Tagging proteomic analysis of the vEC secretome identified significantly increased fibroleukin (FGL2) in conditioned media from HUVECs exposed to arterial FSS. This increase was validated by Western blotting. Application of the NFκB inhibitor BAY 11-7085 (1 µM) following pre-conditioning reduced FGL2 release from vECs exposed to arterial FSS. Exposure of vECs to arterial FSS increased apoptosis, measured by active cleaved caspase-3 (CC3) immunocytochemistry, which was likewise elevated in HUVECs treated with recombinant FGL2 (20 ng/mL) for 24 h under static conditions. To determine the mechanism of FGL2-induced apoptosis, HUVECs were pre-treated with a blocking antibody to FcγRIIB, a receptor FGL2 is proposed to interact with, which reduced CC3 levels. In conclusion, our findings indicate that the exposure of vECs to arterial FSS results in increased release of FGL2 via NFκB signalling, which promotes endothelial apoptosis via FcγRIIB signalling. Therefore, the inhibition of FGL2/FcγRIIB signalling may provide a novel approach to reduce arterial FSS-induced vEC apoptosis in vein grafts and suppress VGF.

Background and Aims: The accumulation of divergent macrophage populations differentially directs tissue injury and reparative processes after acute myocardial infarction (MI), with colony stimulating factors (CSFs) proposed to orchestrate macrophage polarisation towards pro-inflammatory (Csf2) and pro-fibrotic (Csf1) phenotypes. In this study, we evaluated the effect of Csf2 receptor (Csf2ra)-deficiency or inhibition on post-MI remodelling. Methods: We performed proteomics on the secretome of Csf1- and Csf2-polarised human macrophages, and exposed human cardiac fibroblasts to the secretomes, in conjunction with loss-/gain-of-function assays. Additionally, mice with macrophage-specific deletion of Csf2ra (Csf2ra-mac-KO), and C57Bl/6J mice with pharmacological inhibition of Csf2ra, were subjected to LAD-induced MI, alongside relevant controls. Results: The secretome of Csf2-polarised macrophages increased fibroblast migratory and contractile capacity, and proteomics revealed increased Cathepsin Z expression (log-fold-change=2.09) alongside reduced CXCL10 levels (log-fold-change=2.14). Gain-/loss-of-function experiments revealed CXCL10/CXCR3 promoted a reparative fibroblast phenotype, while Cathepsin Z degraded CXCL10. In vivo, Csf2ra mac-KO increased fibroblast (p<0.01) and anti-inflammatory macrophage density (p<0.001) 28-days post-MI, and improved cardiac function (p<0.05). Similarly, Csf2ra inhibition accelerated fibroblast (p<0.05), anti-inflammatory macrophage (p<0.01), and capillary accumulation (p<0.05), which was associated with reduced infarct size (p<0.01) and enhanced cardiac function (p<0.01). Furthermore, Csf2ra inhibition reduced Cathepsin Z levels (p<0.001) and concomitantly increased CXCL10 expression (p<0.05). Conclusions: Together these novel findings reveal Csf2-polarised macrophages drive pro-inflammatory responses post-MI through a Cathepsin-Z/CXCL10-mediated mechanism and crosstalk with cardiac fibroblasts, preventing scar resolution. Providing direct translational potential, our interventional outcomes demonstrate that Csf2ra inhibition accelerates reparative remodelling, through enabling favourable Csf1-driven pro-fibrotic responses and therefore promoting post-MI recovery and limiting heart failure risk.

The long saphenous vein is the most used conduit in cardiac surgery, but its long-term patency is limited by vein graft disease (VGD). Endothelial dysfunction is a key driver of VGD; its aetiology is multi-factorial. However emerging evidence identifies vein conduit harvest technique and preservation fluids as causal in their onset and propagation. This study aims to comprehensively review published data on the relationship between preservation solutions, endothelial cell integrity and function, and VGD in human saphenous veins harvested for CABG. The review was registered with PROSPERO (CRD42022358828). Electronic searches of Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE databases were undertaken from inception until August 2022. Papers were evaluated in line with registered inclusion and exclusion criteria. Searches identified 13 prospective, controlled studies for inclusion in the analysis. All studies used saline as a control solution. Intervention solutions included heparinised whole blood and saline, DuraGraft, TiProtec, EuroCollins, University of Wisconsin (UoW), buffered, cardioplegic and Pyruvate solutions. Most studies demonstrated that normal saline appears to have negative effects on venous endothelium and the most effective preservation solutions identified in this review were TiProtec and DuraGraft. The most used preservation solutions in the UK are heparinised saline or autologous whole blood. There is substantial heterogeneity both in practice and reporting of trials evaluating vein graft preservation solutions, and the quality of existing evidence is low. There is an unmet need for high quality trials evaluating the potential for these interventions to improve long-term patency in venous bypass grafts.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

Background: Osteopontin has been implicated in vascular calcification formation and vein graft intimal hyperplasia, and its expression can be triggered by pro-inflammatory activation of cells. The role of osteopontin and the temporal formation of microcalcification in vein grafts is poorly understood with a lack of understanding of the interaction between haemodynamic changes and the activation of osteopontin. Methods: We used a porcine model of vein interposition grafts, and human long saphenous veins exposed to ex vivo perfusion, to study the activation of osteopontin using polymerase chain reaction, immunostaining, and 18F-sodium fluoride autoradiography. Results: The porcine model showed that osteopontin is active in grafts within 1 week following surgery and demonstrated the presence of microcalcification. A brief pretreatment of long saphenous veins with dexamethasone can suppress osteopontin activation. Prolonged culture of veins after exposure to acute arterial haemodynamics resulted in the formation of microcalcification but this was suppressed by pretreatment with dexamethasone. 18F-sodium fluoride uptake was significantly increased as early as 1 week in both models, and the pretreatment of long saphenous veins with dexamethasone was able to abolish its uptake. Conclusions: Osteopontin is activated in vein grafts and is associated with microcalcification formation. A brief pretreatment of veins ex vivo with dexamethasone can suppress its activation and associated microcalcification.

Background:Endothelial dysfunction is a critical component of both atherosclerotic plaque formation and saphenous vein graft failure. Crosstalk between the pro-inflammatory TNF-α-NFκB signaling axis and the canonical Wnt/β-catenin signaling pathway potentially plays an important role in regulating endothelial dysfunction, though the exact nature of this is not defined. Results:In this study, cultured endothelial cells were challenged with TNF-α and the potential of a Wnt/β-catenin signaling inhibitor, iCRT-14, in reversing the adverse effects of TNF-α on endothelial physiology was evaluated. Treatment with iCRT-14 lowered nuclear and total NFκB protein levels, as well as expression of NFκB target genes, IL-8 and MCP-1. Inhibition of β-catenin activity with iCRT-14 suppressed TNF-α-induced monocyte adhesion and decreased VCAM-1 protein levels. Treatment with iCRT-14 also restored endothelial barrier function and increased levels of ZO-1 and focal adhesion-associated phospho-paxillin (Tyr118). Interestingly, inhibition of β-catenin with iCRT-14 enhanced platelet adhesion in cultured TNF-α-stimulated endothelial cells and in an ex vivo human saphenous vein model, most likely via elevating levels of membrane-tethered vWF. Wound healing was moderately retarded by iCRT-14; hence, inhibition of Wnt/β-catenin signaling may interfere with re-endothelialisation in grafted saphenous vein conduits. Conclusion:Inhibition of the Wnt/β-catenin signaling pathway with iCRT-14 significantly recovered normal endothelial function by decreasing inflammatory cytokine production, monocyte adhesion and endothelial permeability. However, treatment of cultured endothelial cells with iCRT-14 also exerted a pro-coagulatory and moderate anti-wound healing effect: these factors may affect the suitability of Wnt/β-catenin inhibition as a therapy for atherosclerosis and vein graft failure.

Coronary artery bypass grafting remains the treatment of choice for a large cohort of patients with significant coronary disease. Despite the increased use of arterial grafts, the long saphenous vein remains the most commonly used conduit. Long-term graft patency continues to be the Achilles heel of saphenous vein grafts. This is due to the development of intimal hyperplasia, a chronic inflammatory disease that results in the narrowing and occlusion of a significant number of vein grafts. Research models for intimal hyperplasia are essential for a better understanding of pathophysiological processes of this condition. Large animal models resemble human anatomical structures and have been used as a surrogate to study disease development and prevention over the years. In this paper, we systematically review all published studies that utilized large animal models of vein graft disease with a focus on the type of model and any therapeutic intervention, specifically the use of external stents/mesh.

Background The use of vein grafts in coronary artery surgery is complicated by a high late restenosis rate resulting from the development of intimal hyperplasia, and accelerated atherosclerosis. TGFβ has been implicated in the process of intimal hyperplasia but the role of TGFβ driven Endothelial to mesenchymal is not fully understood. Here, we have investigated the hypothesis that arterial shear stress (flow) can trigger Endothelial to mesenchymal changes in venous ECs mediated by TGFβ / SMAD pathway in-vitro and ex-vivo and that a brief pretreatment of vein with Dexamethasone can suppress such changes.Methods and Results Comparative reverse-transcriptase polymerase chain reaction, immunostaining and Western blotting revealed that arterial shear stress induced TGFβ / SMAD dependent in HUVEC which was regulated by TWIST 1&2 as the selective inhibition of TWIST 1 or 2 using specific siRNA suppressed EndMT in response to shear stress. We also noted that brief pretreatment of HUVECs with Dexamethasone can modulate EndMT changes in response to shear stress. Using spatial cell sequencing in human long saphenous vein segments exposed to acute arterial flow identified a cluster of cells that had both EC and SMC phenotypes where TWIST2 was significantly upregulated. We validated the untargeted spatial findings in segments of veins under acute arterial flow ex-vivo using comparative reverse-transcriptase polymerase chain reaction, immunostaining and RNAscope and observed that Dexamethasone can suppress EndMT changes in vein segments by suppressing TGFβ / SMAD/ TWIST1 &2.Conclusion Dexamethasone brief pretreatment can suppress EndMT changes triggered by acute exposure of long saphenous vein segments to arterial haemodynamics by modulating TGFβ / SMAD / TWIST1 &2 pathway.### Competing Interest StatementThe authors have declared no competing interest.### Funding StatementThis study was funded by the Van Geest foundation charitable fund and the BHF accelerator award.### Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The study was approved under Leicester Biomedical Research Centre (BRICCS Ethics Ref: 09/H0406/114). Informed consent was obtained from all study participants prior to surgery and use of human tissue conformed to the principles outlined in the Declaration of Helsinki.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.YesAll data produced in the present study are available upon reasonable request to the authors

Background and Aims: Perpetual monocyte/macrophage recruitment and subsequent foam cell formation characterises advanced atherosclerotic plaques, especially lesions precipitating myocardial infarction and stroke. Recent advances have illuminated macrophage diversity within atherosclerotic plaques, with select populations attributed a deleterious role. Accordingly, novel targets within specific macrophage subsets may yield therapeutic potential. Methods: Next generation sequencing (NGS) was conducted upon stable and unstable human coronary atherosclerotic plaques, alongside divergent monocyte/macrophage subsets (n=5/group). RNA-interference (RNAi) studies were performed using human monocyte-derived macrophages to assess invasion and foam-cell formation. In vivo efficacy of IMSET inhibition on macrophage invasion and progression of atherosclerosis was evaluated in high-fat-fed Apoe-deficient mice, with proteomics deployed to elucidate mechanistic insight. Results: Magnetic bead separation and subsequent NGS revealed two novel LncRNA (ROMBA and IMSET) were significantly upregulated within a pro-inflammatory monocyte subset and increased within foam-cell macrophage-rich unstable human plaques compared to stable lesions. RNAi-directed inhibition of either LncRNA significantly perturbed foam cell formation (p<0.05;n=5) but only IMSET inhibition reduced macrophage invasion in vitro (p<0.01;n=5) and in vivo (p<0.01;n=6). Similarly, IMSET RNAi blocked the progression of pre-existing atherosclerotic plaques within Apoe-deficient mice, as evidenced through reduced lesion size, macrophage density, and lipid-rich/necrotic core area (p<0.001;n=10). Ensuing proteomics revealed a role for IMSET in regulating members of the NFκβ and TGFβ pathways. Conclusions: We have identified a novel LncRNA (IMSET) which facilitates invasion of a deleterious macrophage subset and their transition into foam cells. Pharmacological targeting of IMSET suppresses the progression of established atherosclerosis, identifying its potential as a therapeutic target for the stabilisation of atherosclerotic plaques.