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O066 - Macrophages, Smooth Muscle Cells and Nod1 inhibition in advanced stages of Atherosclerosis: a clue to plaque stabilization and atherothrombosis attenuation (ID 11)

Session Type
Vascular Biology
Session Time
10:30 - 12:00
Date
Wed, 02.06.2021
Room
Live Streamed
Lecture Time
11:11 - 11:19

Abstract

Background and Aims

Macrophages and Smooth Muscle Cells (SMCs) are well known to have a preeminent role in plaque necrosis and rupture. These events, added to inflammation and thin layers of collagen unchain atherothrombosis, the main cause of Acute Coronary Syndromes (ACs). Pattern recognition receptor Nucleotide-Binding Oligomerization Domain-1 (NOD1) has previously been linked to inflammation and cardiovascular diseases. The aim of this work was to unveil the function of NOD1 in the plaque stabilization phenomena in the late stages of the disease.

Methods

Athero-prone Apoe-/-Nod1-/- against Apoe-/-mice were treated with high fat diet for 16 weeks in order to characterized the advanced lesions in the aortic sinus. Proliferation, apoptosis and foam cell formation were assessed in the atheroma lesions and in primary cell cultures of macrophages and vascular SMCs. In addition, human coronary arteries were employed. Cell procedures, flow cytometry, immunofluorescences, histochemistry techniques, qRT-PCR, western blot and kinetic colorimetric assays were performed.

Results

ORO stained aorta showed a reduction in the atheroma of the double-knockout mice. NOD1 staining in human atherosclerotic coronary arteries was enhanced near lipid deposition areas and NOD1 expression was higher in Macrophages (MAC3 marker) and SMCs (Smooth Muscle α-actin marker) of these plaques. We also demonstrated that NOD1 deletion or inhibition reduced myeloid cells infiltration, macrophage and SMCs apoptosis, fibrous caps and collagen content. Interestingly, Nod1-/-SMCs presented higher proliferation rates.

Conclusions

To conclude, here we determine that both macrophages and SMCs are subjected to NOD1 regulation under advanced atherogenesis condition, triggering plaque vulnerability and thus promoting atherothrombosis and ACS.

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O043 - The effect of miR-125a-3p inhibitor on M1/M2 macrophages, MMP-2 and VEGF in atherosclerotic plaque (ID 51)

Session Type
Rapid Fire Session
Session Time
14:30 - 15:30
Date
Tue, 01.06.2021
Room
Hall F
Lecture Time
14:43 - 14:48

Abstract

Background and Aims

Macrophages play a key role in the atherosclerosis, tissue macrophages can be divided into two types, the classical activation type (type M1) and alternative activation type (M2 type). Recent studies show that the balance of M1/M2 plays an important role in atherosclerotic plaque stability. miR-125a-3p can regulate the differentiation of monocytes to M1 type macrophages. In our previous study , the expression of miR-125a-3p was significantly increased in patients with acute coronary syndrome. This study is to investigate the effect of miR-125a-3p inhibitor on the atherosclerotic plaque formation, M1/M2 macrophages, MMP-2 and VEGF in atherosclerotic plaque in vivo.

Methods

Cholesterol-fed rabbits were applied to study the effect of miR-125a-3p inhibitor on atherosclerotic plaque, the area of atherosclerotic plaque was measured by image analysis after oil red O staining, MMP-2 and VEGF were measured by immunohistochemistry, and the M1 marker CD11c and M2 marker CD206 were detected by immunofluorescence in plaque tissue.

Results

Compared with high-cholesterol group, plaque area percentage was significantly decresed in miR-125a-3p inhibitor group. Compared with the control group, the level of MMP-9、VEGF and CD11c were significantly increased in high-cholesterol group and decreased in miR-125a-3p inhibitor group, the level of CD206 was significantly decreased in high-cholesterol group and increased in miR-125a-3p inhibitor group.

Conclusions

Inhibition of miR-125a-3p could attenuate the development of atherosclerotic plaque, balance of M1/M2 macrophages, and decrease of MMP-9 and VEGF in plaque tissue. miR-125a-3p may be a new targets for the treatment of unstable plaque.

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O072 - Colchicine suppresses atherosclerotic plaque development and modulates atherogenic vascular smooth muscle cell and monocyte behaviour (ID 52)

Session Type
Vascular Biology
Session Time
17:00 - 18:30
Date
Wed, 02.06.2021
Room
Live Streamed
Lecture Time
17:57 - 18:05

Abstract

Background and Aims

Atherosclerosis is a chronic inflammatory process involving multiple different cells including monocytes and smooth muscle cells. There is accumulating evidence suggesting that colchicine might be beneficial in these patients with atherosclerosis however, its specific mechanism of action on plaque cells remains unclear.

Methods

Apolipoprotein E knockout mice (ApoE-/-) on a high fat diet were treated with daily intraperitoneal injections of Colchicine or PBS for 16 weeks. The aorta was harvested for en face staining, immunostaining, and qPCR analysis. Human Peripheral Blood Monocytes (HPBM) and Human Coronary Artery Smooth Muscle Cells (HCASMC) from healthy donors were treated with Colchicine In Vitro. HPBM were also isolated from Acute Coronary Syndrome (ACS) patients and treated with Colchicine In Vitro.

Results

Colchicine treated ApoE-/- mice had decreased atherosclerotic plaque burden and lipid content on en face staining of the aorta. There was also a decrease in CD68+ cells within atherosclerotic plaques. Colchicine treated mice also had lower pro-inflammatory transcript levels of IL-1β, TNF-α, IL-6 and MCP-1. LPS stimulated HPBM that were treated with Colchicine demonstrated a decrease in TNF-α and MCP-1 gene and protein expression. In Vitro treatment of HCASMC with Colchicine demonstrated decreased cholesterol and oxidised LDL (ox-LDL) uptake as well as decreased IL-6 and MCP-1 transcript levels. There was also a reduction in HCASMC proliferation, migration and lipid uptake when cultured in Colchicine treated LPS-stimulated Monocyte secreted media from healthy controls and ACS patients.

Conclusions

Colchicine treatment decreases atherogenesis in a murine model of atherosclerosis and demonstrated anti-inflammatory effects on monocytes and smooth muscle cells.

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O052 - Z-Ligustilide protects vascular endothelial cells from oxidative stress and rescues high fat diet-induced atherosclerosis by activating multiple NRF2 downstream genes (ID 53)

Session Type
Genetics
Session Time
14:30 - 16:00
Date
Tue, 01.06.2021
Room
Hall D
Lecture Time
15:20 - 15:28
Presenter

Abstract

Background and Aims

Oxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerosis. In the present work, we appraise the cytoprotective property and anti-atherosclerosis effect of Z-Ligustilide (Z-Lig), which is derived from the Ligusticum species.

Methods

Potential NRF2 activators were screened and verified by luciferase reporter gene assay. The protein and mRNA levels of NRF2 and ARE-mediated genes, and GSH/GSSG level in EA.hy926 cells treated with Z-Lig were detected. The cytoprotective property of Z-Lig was assessed in the tert-butyl hydroperoxide (t-BHP)-evoked oxidative stress model. Cell viability and reactive oxygen species (ROS) levels in EA.hy926 cells were determined. An atherosclerosis model induced by HFD was used to determine the anti-atherosclerosis effect of Z-Lig in HFD-fed Ldlr-deficient mice.

Results

In vitro, 100 μM Z-Lig upregulated expressions of NRF2 and ARE-driven genes, promoted accumulation of nuclear NRF2 and unbound NRF2- KEAP1 complex in EA.hy926 cells. Furthermore, Z-Lig alleviated oxidative stress and cell injury caused by t-BHP via stimulation of the NRF2/ARE pathway. In vivo, intervention with 20 mg/kg Z-Lig markedly restrained atherosclerosis progression, including attenuation of HFD-induced atherosclerotic plaque formation, alleviation of lipid peroxidation and increase in antioxidant enzyme activity in aortas of HFD-fed Ldlr-/- mice. The chemopreventive effects of Z-Lig might be associated with the activation of NRF2 and ARE-driven genes.

Conclusions

The present study suggested that Z-Lig is an effective NRF2 activator, which can protect vascular endothelial cells from oxidative stress and rescue HFD-induced atherosclerosis.

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O046 - Tissue-specific functional interaction between apolipoproteins A1 and E in cold-induced adipose organ mitochondrial energy metabolism. (ID 60)

Session Type
Rapid Fire Session
Session Time
14:30 - 15:30
Date
Tue, 01.06.2021
Room
Hall F
Lecture Time
14:58 - 15:03

Abstract

Background and Aims

White (WAT) and brown (BAT) adipose tissue, are respectively responsible for lipid storage and non-shivering thermogenesis, a process mediated by mitochondrial uncoupling protein 1 (UCP1) which uncouples oxidative phosphorylation from ATP production, leading to heat production. This process can be triggered by cold exposure, caloric excess, and the immune system. Recently thermogenesis has been associated with plasma lipoprotein transport system. Specifically, APOE3 is shown to have a bimodal effect on WAT thermogenesis while APOE2 and APOE4 differentially affect BAT and WAT thermogenesis in processes highly modulated by APOA1. Furthermore, APOA1 deficiency is associated with no measurable UCP1 levels in WAT of mice fed high fat diet.

Methods

Based on these observations here we sought to investigate the potential roles of APOA1 and APOE3 in BAT and WAT metabolic activation in mice, following a 2-week stimulation by cold exposure (7oC).

Results

Our data showed that APOA1 deficiency ablated BAT and WAT mitochondrial metabolic response to cold stimuli. Ectopic expression of APOA1 in Apoa1-/- mice exposed to 7oC, resulted in virtually undetectable levels of APOE-containing HDL and only BAT thermogenesis induction. On the contrary, WAT mitochondria responded to cold stimuli only under the concomitant expression of both APOA1 and APOE3 in these mice.

Conclusions

In conclusion, APOA1-containing HDL promotes BAT thermogenesis in the presence of very low levels of APOE3-containing HDL, which acts as an inhibitor in this process. In contrast, induction of WAT thermogenesis is subjected to a more complicated regulation which requires the presence of both APOA1- and APOE3-containing HDL.

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O042 - Soluble endoglin as a potential biomarker of NASH development, participating in aggravation of NASH-related changes in mouse liver (ID 107)

Session Type
Rapid Fire Session
Session Time
14:30 - 15:30
Date
Tue, 01.06.2021
Room
Hall F
Lecture Time
14:38 - 14:43

Abstract

Background and Aims

Nonalcoholic steatohepatitis (NASH) is characterized by hepatic steatosis with inflammation and fibrosis. Membrane endoglin (Eng) is shown to participate in fibrosis, and plasma concentrations of soluble endoglin (sEng) are increased in patients with hypercholesterolemia and type 2 diabetes mellitus. We hypothesize that NASH increases both hepatic Eng expression and sEng in blood, and that high levels of sEng modulate cholesterol and bile acid (BA) metabolism and affect NASH progression.

Methods

Three-month-old transgenic male mice overexpressing human sEng and their wild type littermates are fed for six months with either a high-saturated fat, high-fructose high-cholesterol (FFC) diet or a chow diet. Evaluation of NASH, LC-MS analysis of BA, hepatic expression of Eng, inflammation, fibrosis markers, enzymes and transporters involved in hepatic cholesterol and BA metabolism are assessed using qRT-PCR and Western blot.

Results

The FFC diet significantly increased mouse sEng levels and hepatic expression of Eng. High levels of human sEng resulted in increased hepatic deposition of cholesterol due to reduced conversion into BA, as well as redirected the metabolism of triglycerides (TAG) to its accumulation in the liver, via reduced TAG elimination by beta-oxidation combined with reduced hepatic efflux.

Conclusions

We propose that sEng might be a biomarker of NASH development, and the presence of high levels of sEng might support NASH aggravation by impairing the essential defensive mechanism protecting NASH liver against excessive TAG and cholesterol accumulation, suggesting the importance of high sEng levels in patients prone to develop NASH.

Supported by Ministry of Health of the Czech Republic grant AZV 17-31754A and GAUK No.1166119.

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O007 - Replacement of dietary SFA with unsaturated fatty acids has favourable effects on platelet function: The Reading, Imperial, Surrey Saturated Fat Cholesterol Intervention (RISSCI)-1 study (ID 137)

Session Type
Lipoproteins and Metabolism
Session Time
11:30 - 13:00
Date
Mon, 31.05.2021
Room
Live Streamed
Lecture Time
12:03 - 12:11

Abstract

Background and Aims

Background: Inappropriate activation of platelet function is known to promote arterial thrombosis leading to myocardial infarction and ischaemic stroke. Dietary fat composition may represent an important modulator of platelet activation, but underlying mechanisms are unclear.

Aim: To determine the effects of replacement of dietary saturated fatty acids (SFA) with unsaturated fatty acids (UFA) on platelet function in healthy men.

Methods

Methods: In this secondary analysis of the RISSCI-1 study (ClinicalTrials.gov Identifier: NCT03270527), platelet function analysis was performed in a subgroup of men (n=51) at the University of Reading. Participants followed two sequential isoenergetic diets for 4 weeks each: high-SFA (18% of total energy (TE)) and low-SFA (≤10%TE). Light transmission platelet aggregometry and flow cytometric measurement of platelet P-selectin exposure, and fibrinogen binding were measured in response to a series of agonists at the end of each intervention diet. Platelet sensitivity to the agonists was established by calculating the EC50.

Results

Results: Platelet sensitivity to a collagen receptor (GPVI) selective agonist was increased after the high compared with low SFA diet (P=0.007)(P-selectin binding, EC50). A significant increase in the extent of platelet aggregation and the capacity to bind fibrinogen in response to ADP were also evident after the high compared with low SFA diet (P≤0.025). Platelet count increased, whereas platelet size decreased in whole blood after the high than low SFA diet (P≤0.01).

Conclusions

Conclusion: Our findings suggest that replacement of dietary SFA with UFA may have beneficial effects on platelet activation by decreasing the expression of P-selectin, fibrinogen binding and reducing platelet aggregation.

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O036 - Differential Effects of Omega-3 Fatty Acids on Lipopolysaccharide (LPS)-induced Macrophage Activation in Combination with COX inhibition (ID 138)

Session Type
Lipoproteins and Metabolism
Session Time
12:30 - 14:00
Date
Tue, 01.06.2021
Room
Hall B (Live Q&A)
Lecture Time
13:00 - 13:08

Abstract

Background and Aims

Macrophages contribute to chronic diseases by promoting inflammation. Macrophage activation results in increased inducible nitric oxide synthase (iNOS) expression which can be modulated by cyclooxygenase (COX) activity. As both a substrate and potential inhibitor of COX activity, the omega-3 fatty acid EPA may modulate iNOS activity. We investigated the effect of EPA and DHA on iNOS activity in LPS-activated macrophages.

Methods

Murine J774 macrophages were pretreated with vehicle, EPA or DHA over a range of concentrations (1.9µM-50µM) during a challenge with lipopolysaccharide (LPS) at 1.0 µg/ml in DMEM supplemented with 1% FCS. After 24 hr, iNOS activity was assessed by nitrite production using the Griess assay. As a positive control, nitrite measurements with EPA and DHA were compared in combination with the COX inhibitor diclofenac at 100 µM.

Results

Macrophage treatment with LPS increased nitrite levels. EPA treatment reduced LPS-induced nitrite production in a concentration-dependent manner with statistically significant reductions (Figure 1). The inhibitory effects of EPA on iNOS activity were significantly (p<0.0001; two-way ANOVA with Sidak’s multiple comparisons test, n=9) enhanced at all concentrations in the presence of diclofenac. By contrast, DHA did not significantly reduce LPS induced iNOS activity either in the absence or presence of diclofenac.epa inhibits lps-induced nitrite release that is enhanced with diclofenac.jpg

Conclusions

Our observations that EPA but not DHA reduced macrophage iNOS activity may contribute to our understanding of the reduced cardiovascular events as reported in the REDUCE-IT trial with an EPA only formulation. The ability of EPA to modulate macrophage activity has therapeutic implications for patients with cardiovascular risk.

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O037 - Dietary omega-3 fatty acid reverses age-linked heart failure with preserved ejection fraction (ID 158)

Session Type
Lipoproteins and Metabolism
Session Time
12:30 - 14:00
Date
Tue, 01.06.2021
Room
Hall B (Live Q&A)
Lecture Time
13:08 - 13:16

Abstract

Background and Aims

Heart failure with preserved ejection fraction (HFpEF) is the most common type of HF in aged adults, yet no optimal pharmacological therapy has emerged for improved outcomel in HFpEF. Therefore, there is an urgent need for novel effective interventions in the age‐related HFpEF. The plant-derived omega-3-fatty-acid α-linolenic-acid (ALA) has emerged to confer potential protective effects in cardiovascular disease. Our recent findings reveal that lifelong dietary ALA dampens thrombotic and cerebrovascular events in aged mice. The purpose of this study was to elucidate the reversal of age-related HFpEF phenotype by long-term nutritional ALA supplementation.

Methods

6-month-old (young) wild-type C57BL/6J mice were fed a low, as control, or high ALA diet for more than 12 months. Here, we show that aged (>18 months) mice on low ALA diet recapitulate major hallmarks of HFpEF, including diastolic dysfunction with preserved left ventricular ejection fraction, cardiac interstitial fibrosis, impaired acetylcholine-induced relaxation of aortic segments, and arterial stiffness.

Results

Intriguingly, we revealed that long-term ALA-rich diet reverses diastolic dysfunction, vascular relaxation capacity, reduced pulse wave velocity, interstitial cardiac fibrosis, and coincident hemodynamic abnormalities in aged mice. These findings are accompanied by blunting of inflammatory responses and a remarkable reduction in the expression of matrix-metalloproteinase-2 (MMP-2) by high ALA diet.

Conclusions

Our results demonstrate previously unrecognized protective effects of dietary ALA against impaired cardiovascular functional outcomes and cardiac structural changes typical of HFpEF in aged mice. Taken together, these data support the ALA-based nutritional intervention as a safe, plant derived and easily accessible therapeutic strategy for age-related HFpEF.

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O031 - Concomitant glucose-dependent insulinotropic receptor (GIPR) and glucagon-like peptide-1 receptor (GLP1R) agonism stimulates TG-rich lipoprotein metabolism and attenuates atherosclerosis development (ID 160)

Session Type
Lipoproteins and Metabolism
Session Time
16:00 - 17:30
Date
Mon, 31.05.2021
Room
Hall C
Lecture Time
16:57 - 17:05

Abstract

Background and Aims

Tirzepatide, a dual GIP/GLP-1 receptor agonist, was recently shown to cause robust weight loss in patients with Type II Diabetes (Frias et al. 2018). Since GIPR agonism stimulates lipolysis in white adipose tissue and GLP1R agonism promotes brown adipose tissue (BAT) thermogenesis, we hypothesized that combining GIPR and GLP1R agonism enhances the fatty acid (FA) flux to BAT to facilitate thermogenesis, thereby alleviating dyslipidemia and atherosclerosis development.

Methods

Dyslipidemic Western-type diet fed female APOE*3-Leiden.CETP mice were subcutaneously injected with either vehicle, a GIPR agonist (GIPFA-085; 300 nmol/kg/day), a GLP1R agonist (GLP-140; 30 nmol/kg/day) or both agonists for up to 10 weeks. Plasma triglyceride (TG) levels were measured, and TG-rich lipoprotein (TRL) metabolism was assessed using injection of glycerol tri[3H]oleate and [14C]cholesteryl oleate-labeled TRL-like particles. In the aortic valve region, atherosclerotic lesions were scored.

Results

GLP1R agonism lowered body weight (-2.0 g) and increased the uptake of VLDL-TG-derived FA by BAT (+157%) compared to vehicle. On these parameters concomitant GIPR and GLP1R agonism outperformed GLP1R agonism alone (body weight -2.8 g; VLDL-TG derived FA uptake by BAT +191%). Concomitant GIPR and GLP1R agonism, but not GLP1R agonism or GIPR agonism alone, tended to lower plasma TG levels (-46%) and markedly increased hepatic TRL-remnant uptake (+67%). Importantly, concomitant GIPR and GLP1R agonism decreased atherosclerotic lesion progression (-35% severe lesions).

Conclusions

Concomitant GIPR and GLP1R agonism stimulates TRL lipolysis and clearance more than the individual agonists and correspondingly attenuates atherosclerosis development. Current studies evaluate the effects of co-treatment on atherosclerosis in an obese setting.

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O070 - Coronary Artery Calcium score and SAFEHEART-Risk Equation for risk stratification in primary prevention familial hypercholesterolemia. (ID 173)

Session Type
Vascular Biology
Session Time
17:00 - 18:30
Date
Wed, 02.06.2021
Room
Live Streamed
Lecture Time
17:41 - 17:49

Abstract

Background and Aims

Common cardiovascular risk equations are imprecise for heterozygous Familial Hypercholesterolemia (HeFH). Coronary Artery Calcium (CAC) score could help to better stratify the risk of major cardiovascular events (MACE). We investigated the additional contribution of CAC Score to SAFEHEART risk equation (SAFEHEART-RE) for MACE prediction in HeFH.

Methods

We analyzed data from primary prevention HeFH patients undergoing CAC quantification from two ongoing national registries , REFERCHOL and SAFEHEART. CAC score was expressed as log(CAC + 1).We used probability-weighted Cox proportional hazard models to estimate hazard ratios (HR). Area under the receiver operator characteristic curve (AUC) and net reclassification improvement (NRI) were used to compare incremental contribution of CAC score to SAFEHEART-RE for MACE prediction. MACE were defined as coronary heart disease, stroke or transient ischemic attack, peripheral artery disease, resuscitated sudden death and cardiovascular death.

Results

We included 1424 patients (age 48.9±12.8, men 45.9%).

After a 2.4-years follow-up, MACE occurred in 70 subjects. The addition of log(CAC+1) to SAFEHEART-RE was associated with an improved prediction of MACE in intermediate-risk (from HR 3.2 [95%CI 1.77-5.59] to HR 8.18 [95%CI 3.26-20.37]) and in high-risk subjects (from HR 3.5 [95%CI 1.93-6.30] to HR 20.21 [95%CI 8.58-47.6]) (log-rank p <0.0001). The c-statistics confirmed a significant improvement in MACE prediction by the addition of log(CAC+1) to SAFEHEART-RE (AUC 0.896 [0.889-0.903]) versus SAFEHEART-RE alone (AUC 0.859 [0.852-0.866]) (p= 0.004). The addition of CAC score was associated with an overall NRI of 46.8%.

table and figure.png

Conclusions

Identification of very-high risk HeFH patients is possible by combining information from SAFEHEART-RE and CAC score.

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O068 - Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury (ID 194)

Session Type
Vascular Biology
Session Time
10:30 - 12:00
Date
Wed, 02.06.2021
Room
Live Streamed
Lecture Time
11:27 - 11:35

Abstract

Background and Aims

Background and Aims: Vascular smooth muscle cells (VSMCs) accumulate in injury-induced neointimal lesions and atherosclerotic plaques in an oligoclonal fashion, yet plaque VSMCs show reduced proliferation and cell senescence. DNA damage leads to VSMC senescence and inflammation and VSMC senescence promotes atherosclerosis; however, the exact mechanism by which VSMC senescence promotes lesion formation is not known. Here, we investigated telomere damage-induced VSMC senescence, the contribution of senescence-induced inflammation and the mechanisms involved, the consequences of VSMC senescence in vivo after injury, and whether it promotes clonality.

Methods

Methods: Stress-induced premature senescence (SIPS) was induced by doxorubicin (24h treatment+21d recovery). Lentiviruses were used to stably overexpress a dysfunctional TRF2 mutant protein (TRF2T188A) in hVSMCs. SM22αTRF2T188A mice were generated that express human TRF2T188A in VSMCs only, and crossed with Myh11-CreERT2 Rosa26-Confetti multicolour reporter mice to examine cell senescence and clonality in vivo.

Results

Results: Both SIPS and TRF2188A-induced VSMC senescence were characterised by persistent telomere damage, and associated with formation of micronuclei, activation of cGAS-STING cytoplasmic DNA sensing, and induction of multiple pro-inflammatory cytokines. Silencing of cGAS in TRF2T188A hVSMCs partially inhibited NFκB-dependent cytokine expression. In vivo, VSMC-specific TRF2T188A expression in a multicolour VSMC-tracking model demonstrated no change in VSMC clonal patches after injury, but increased neointima formation, outward remodelling, and immune/inflammatory cell infiltration or retention.

Conclusions

Conclusion: Persistent telomere damage promotes VSMC senescence and inflammation and exacerbates neointima formation after injury. Our data suggest that persistent telomere damage-induced VSMC senescence plays a major role in driving inflammation through immune cell recruitment in vascular disease.

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