Atherosclerotic Plaque Stability Research Articles

Influence of ferroptosis indicators on the stability of atherosclerotic plaque.

Ferroptosis is a new form of cell death that is unique and closely related to iron concentration, and reactive oxygen species (ROS) production. We investigated the indicators of ferroptosis between vulnerable plaque and stable plaque in atherosclerotic. Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting were used to detect the expression of the ferroptosis-related genes and proteins and extracellular matrix stability-related genes and proteins (FN, CoL-1). Superoxide dismutase (SOD) activities, glutathione peroxidase (GSH) and malondialdehyde (MDA) were detected by ELISA. The commercially available kit was used to detect Fe2+ concentration in tissue. DCFH-DA fluorescent probe was used to detect the ROS levels. H&E stain, Masson trichrome stain, and Oil Red O stain were used to detect pathological states in vulnerable plaque and stable plaque. Tissue localization and positive rate of GPX4, SLC7A11, COX-2, FN, and COL-1 were evaluated by immunohistochemistry. The results showed a significant increase in the expression of COX2 and a significant decrease in the expression of GPX4 and SLC7A11 in genes related to ferroptosis in vulnerable plaque compared with stable plaque. Pathologic results showed vulnerable plaque with higher levels of inflammatory cell infiltration, more diffuse collagen fibers, and larger particles of lipid droplets. Concentrations of the antioxidant metabolites SOD and GSH were significantly reduced and concentrations of the oxidative metabolites MDA and Fe2+ were significantly increased in vulnerable plaque compared with stable plaque. The expression of FN and CoL-1 was significantly reduced in genes related to extracellular matrix stability in vulnerable plaque. Taken together, these findings indicate that the degree of ferroptosis in vulnerable plaque is higher than that in stable plaque, suggesting that changes in indicators of ferroptosis may affect carotid atherosclerotic plaque stability, target spot in the ferroptosis signaling pathway may provide further theoretical basis for the clinical treatment of carotid atherosclerosis.

Suppression of endoplasmic reticulum stress by 4-PBA enhanced atherosclerotic plaque stability via up-regulating CLOCK expression

Endoplasmic reticulum (ER) stress refers to a condition where the normal functioning of the ER is disrupted due to a variety of cellular stress factors. As a result, there is an accumulation of unfolded and misfolded proteins within the ER. Numerous studies have shown that ER stress can exacerbate inflammatory reactions and contribute to the development of various inflammatory diseases. However, the role of ER stress in the stability of atherosclerotic plaques remains poorly understood. In this study, we aimed to explore the potential impact of a specific ER stress inhibitor known as 4-phenyl butyric acid (4-PBA) on atherosclerosis in mice. The mice were fed a high-fat diet, and treatment with 4-PBA significantly improved the stability of the atherosclerotic plaques. This was evidenced by a reduction in oxidative stress and an increase in circadian locomotor output cycles kaput (CLOCK) protein and mRNA expression within the plaques. Additionally, 4-PBA reduced the expression of ER stress-related proteins and decreased apoptosis in the atherosclerotic plaques. In vitro investigation, we observed the effect of 4-PBA on vascular smooth muscle cells (VSMCs) that were exposed to oxidized low-density lipoprotein (ox-LDL), a significant contributor to the development of atherosclerosis. 4-PBA reduced reactive oxygen species (ROS) production and attenuated apoptosis, GRP78 and CHOP protein expression in ox-LDL-Induced VSMCs via up-regulating CLOCK expression. However, when the short hairpin RNA against CLOCK (sh-CLOCK) was introduced to the VSMCs, the protective effect of 4-PBA was abolished. This suggests that the up-regulation of CLOCK expression is crucial for the beneficial effects of 4-PBA on atherosclerotic plaque stability. This finding suggests that targeting ER stress and modulating CLOCK protein levels might be a promising way to enhance the stability of atherosclerotic plaques.

Hypercoagulability impairs plaque stability in diabetes-induced atherosclerosis

Abstract Introduction Diabetes mellitus, which is largely driven by nutritional and behavioral factors, is characterized by accelerated atherosclerosis with impaired plaque stability. Atherosclerosis and associated complications are the major cause of mortality in diabetic patients. Efficient therapeutic concepts for diabetes-associated atherosclerosis are lacking. Atherosclerosis among diabetic patients is associated with reduced endothelial thrombomodulin (TM) expression and impaired activated protein C (aPC) generation. Methadology Female ApoE-/- or TMPro/Pro ApoE-/- mice (age 6 to 8 weeks) were fed a normal chow diet and were made diabetic (DM) by injecting streptozotocin, reflecting type 1 DM. After 22 weeks of age, the body weight of the mice was measured, and the mice were sacrificed. Plasma and tissue samples were analysed for different parameters. Results Here, we demonstrate that atherosclerotic plaque stability is reduced in hyperglycemic mice expressing dysfunctional TM (TMPro/Pro mice), which have a pro-coagulant phenotype due to impaired thrombin inhibition and markedly reduced aPC generation. The vessel lumen and plaque size of atherosclerotic lesions in the truncus brachiocephalic were decreased in diabetic TMPro/Pro ApoE-/- mice compared to diabetic ApoE-/- mice. While lipid accumulation in lesions of diabetic TMPro/Pro ApoE-/- mice was lower than that in diabetic ApoE-/- mice, morphometric analyses revealed more prominent signs of instable plaques, such as a larger necrotic core area and decreased fibrous cap thickness in diabetic TMPro/Pro ApoE-/- mice. Congruently, more macrophages and fewer smooth muscle cells were observed within lesions of diabetic TMPro/Pro ApoE-/- mice. Conclusion Thus, impaired TM function reduces plaque stability, a characteristic of hyperglycemia-associated plaques, thus suggesting the crucial role of impaired TM function in mediating diabetes-associated atherosclerosis.

Role of S100A4 in the crosstalk between smooth muscle and inflammatory cells in atherosclerosis

Abstract Background During atherosclerotic plaque formation, smooth muscle cells (SMCs) accumulate in the intima and undergo a transition from a contractile to a synthetic phenotype. We previously showed that S100A4 is a marker of the synthetic SMCs in vitro and intimal SMCs in pig, human and mouse. In vitro, S100A4-treated SMCs acquire a pro-inflammatory phenotype. The systemic neutralization of extracellular S100A4 in ApoE-/- mice induces atherosclerotic plaque stabilization. Purpose To characterize the role of S100A4-expressing SMCs in atherosclerosis. Methods and results We established a coculture model between S100A4-stimulated human aortic SMCs and human blood-derived monocytes. Flow cytometry analysis of monocytes exposed to S100A4-treated SMCs for 3 days showed an upregulation of markers typical of inflammatory M1 (HLA-DR) and anti-inflammatory M2 (CD206) macrophages (fig. 1). Macrophages also upregulated mRNA expression of NPC Intracellular cholesterol transporter 1 and 2 by qPCR, suggesting modifications in their cholesterol metabolism. In vivo, in an SMC-lineage-tracing ApoE-/-mouse model, we identified S100A4-expressing SMCs at the onset of atherosclerosis in aortic media of 11-week-old mice fed a high cholesterol diet (HCD) for 3 weeks. Medial SMCs were characterized by means of single-cell RNA sequencing. Interestingly, 10 out of 11 identified clusters expressed S100A4, demonstrating broad and early involvement of S100A4 in shaping medial SMC identity. We assumed that blood-derived monocytes might be a driving force of early S100A4 activation in SMCs. To mitigate the impact of monocytes, 8-week-old ApoE-/- mice were fed an HCD for 9 weeks and injected with either clodronate-encapsulated or empty liposomes during the first 3 weeks. No differences in S100A4 expression in the media were observed by qPCR. Unexpectedly, ApoE-/- mice treated with clodronate demonstrated larger atherosclerotic lesions compared to control animals as measured by OilRedO staining (fig. 2). Studies are in progress to define the plaque composition. Conclusion Our findings shed light on the role of S100A4 in the crosstalk between SMCs and inflammatory cells in atherosclerosis and the fine-tuning of the phenotype of medial SMCs prior to their accumulation in the intima. We suggest that temporary monocyte depletion at the onset of the disease alters the mechanisms underlying plaque formation, worsening the outcome of the disease, while not affecting S100A4 expression in medial SMCs.

LIGHT/TNFSF14 levels in carotid atherosclerotic plaques are associated with symptomatic cerebrovascular disease

Abstract Background Plaque rupture is the underlying cause of most cardiovascular events, such as stroke and myocardial infarction. Co-stimulatory molecules, the immune checkpoints, are emerging as strong candidates to battle atherosclerosis progression. The co-stimulatory molecule LIGHT (tumour necrosis factor 14; TNFSF14) exists in foam cell-rich regions of atherosclerotic plaques, but whether it has a driving role in promoting a high-risk plaque phenotype is not known. Purpose This study investigates the association between intra-plaque LIGHT and plaque vulnerability. Methods Plaque levels of LIGHT/TNFSF14 were measured in homogenised carotid endarterectomy plaques by Proximity Extension Assay (PEA) in subjects from the Carotid Plaque Imaging Cohort (CPIP; N=201). Homogenates were further examined by multi-plex cytokine analysis and ELISA, and tissue plaque sections through histology/immunohistochemistry. Results Plaque levels of LIGHT were associated with the occurrence of pre-operative cerebrovascular symptoms (p=0.00014). Furthermore, LIGHT correlated strongly with the histological plaque vulnerability index (p=5x10-15): a ratio between the sum of destabilising versus stabilising plaque components (i.e. macrophages, intra-plaque haemorrhage and lipids versus smooth muscle cells and collagen) as well as with necrotic core size and the inflammatory cytokines interleukin(IL)-1β, IL-6, chemokine (C-C motif) ligand (CCL)-2, CCL4 and CCL5. Moreover, plaque LIGHT levels correlated with several components of the extracellular matrix turnover machinery, including cleaved collagen, the collagen cross-linking proteoglycans fibromodulin and lumican, the matricellular protein COMP (cartilage oligomeric matrix protein), and the remodelling regulator ADAMTS7 (a disintegrin and metalloproteinase with thrombospondin motifs-7). Levels also correlated with matrix metalloproteinases (MMPs) 1, 2, 9 and 10, and tissue inhibitor of metalloproteinase (TIMP)-1. Conclusion Expression of LIGHT in atherosclerotic plaques does not only correlate with markers of plaque destabilisation¸ but is also significantly elevated in plaques from symptomatic, compared to asymptomatic, patients. These results connect LIGHT content to a rupture-prone plaque phenotype and suggest the LIGHT signalling pathway as a potential therapeutic target to promote atherosclerotic plaque stability.

CSL112 (apolipoprotein A-I [human]) reduces the elevation in neutrophil-lymphocyte ratio (NLR) induced by acute myocardial infarction

Abstract Background CSL112 (apolipoprotein A-I [human]) is a novel therapy designed to reduce the risk of recurrent cardiovascular events following acute myocardial infarction (AMI). Preclinical data suggest that apolipoprotein A-I has anti-inflammatory properties which might contribute to atherosclerotic plaque stabilization (1). The neutrophil-lymphocyte ratio (NLR) is a clinically accessible measure of inflammatory status and predicts incident cardiovascular events in large outcome trials (2). It is unknown whether CSL112 can reduce inflammation as measured by the NLR. Purpose To evaluate whether infusion of CSL112 inhibits post-AMI inflammation as measured by NLR. Methods In a Phase 2 multicenter, double-blind study, 83 AMI patients with stage 3 chronic kidney disease were randomized 2:1 to receive 4 infusions of either 6 g CSL112 (n=55) or saline placebo (n=28) each separated by one week. The first infusion delivered on protocol Day 1 occurred 12h to 7d after presentation (mean 83 h). Blood samples were drawn prior to each infusion on Days 1, 8, 15 and 22 as well as at both Day 29 and 60 post the first infusion. Leukocyte data were available for up to 75 participants across the 6 sampling timepoints and neutrophil and lymphocyte counts were measured at the central laboratory. NLR was calculated and found to be non-normal in distribution and so analyses were performed on Loge transformed data. A mixed model repeated measures (MMRM) analysis was used to compare change from baseline (Day 1) in LogeNLR, neutrophil count and lymphocyte count between treatment groups (CSL112 6g versus Placebo) at the other 5 timepoints. An analysis of covariance (ANCOVA) was used to assess the effect of time from index MI to first infusion on change from baseline (Day 1) in LogeNLR at Day 8. Results The LogeNLR increased after AMI (between Day 1 and Day 8) with placebo treatment, whereas CSL112 infusion given after the Day 1 blood sample resulted in a decline (p=0.012; Fig 1, left panel, mean±SD). This effect of CSL112 was driven by reduction in neutrophil count (p=0.002; Fig 1, right panel) with lymphocyte levels remaining stable (p=0.537). Importantly, the magnitude of the effect of CSL112 to reduce NLR was greater if the timing of administration was closer to the index MI (treatment X time interaction and treatment effect both p=0.008). Conclusion CSL112 inhibits post-AMI elevation in NLR and this effect is maximized when infusion occurs early after presentation. It remains to be determined whether these anti-inflammatory effects of CSL112, in conjunction with previously demonstrated enhancement in cholesterol efflux capacity, will improve cardiovascular outcomes (3).Fig 1: Change in LogeNLR from baseline

Vitamin E Supplementation and Cardiovascular Health: A Comprehensive Review.

This article conducts a thorough investigation into the potential role of vitamin E in preventing cardiovascular diseases (CVDs) in the context of shifting mortality patterns from infectious diseases to the continued prominence of CVDs in modern medicine. The primary focus is on vitamin E's antioxidant properties and its specific ability to counter lipid peroxidation, a pivotal process in the early stages of atherosclerosis, a precursor to CVDs. The research spans a wide range of methodologies, including in vitro, in vivo, clinical, and experimental studies, examining how vitamin E affects critical aspects of cardiovascular health, such as signaling pathways, gene expression, inflammation, and cholesterol metabolism. It also explores vitamin E's influence on complex processes like smooth muscle cell development, oxidative stress reduction, foam cell formation, and the stability of atherosclerotic plaques. In the context of clinical studies, the article presents findings that both support and yield inconclusive results regarding the impact of vitamin E supplementation on CVDs. It acknowledges the intricate interplay of factors such as patient selection, pathophysiological conditions, and genetic variations, all of which can significantly influence the efficacy of vitamin E. The article underscores the need for ongoing research, with a specific focus on understanding the regulatory metabolites of vitamin E and their roles in modulating cellular processes relevant to CVDs. It highlights the potential for innovative therapeutic approaches based on a deeper comprehension of vitamin E's multifaceted effects. However, it also candidly addresses the challenges of translating clinical trial findings into practical applications and emphasizes the importance of considering diverse variables to optimize therapeutic outcomes. In summary, this meticulously conducted study provides a comprehensive examination of vitamin E's potential as a preventive agent against CVDs, recognizing the complexity of the subject and the need for continued research to unlock its full potential in cardiovascular health.

Protocatechuic aldehyde increases pericyte coverage and mitigates pericyte damage to enhance the atherosclerotic plaque stability

Pericyte dysfunction and loss contribute substantially to the destabilization and rupture of atherosclerotic plaques. Protocatechuic aldehyde (PCAD), a natural polyphenol, exerts anti-atherosclerotic effects. However, the effects and mechanisms of this polyphenol on pericyte recruitment, coverage, and pericyte function remain unknown. We here treated apolipoprotein E-deficient mice having high-fat diet-induced atherosclerosis with PCAD. PCAD achieved therapeutic effects similar to rosuvastatin in lowering lipid levels and thus preventing atherosclerosis progression. With PCAD administration, plaque phenotype exhibited higher stability with markedly reduced lesion vulnerability, which is characterized by reduced lipid content and macrophage accumulation, and a consequent increase in collagen deposition. PCAD therapy increased pericyte coverage in the plaques, reduced VEGF-A production, and inhibited intraplaque neovascularization. PCAD promoted pericyte proliferation, adhesion, and migration to mitigate ox-LDL-induced pericyte dysfunction, which thus maintained the capillary network structure and stability. Furthermore, TGFBR1 silencing partially reversed the protective effect exerted by PCAD on human microvascular pericytes. PCAD increased pericyte coverage and impeded ox-LDL-induced damages through TGF-β1/TGFBR1/Smad2/3 signaling. All these novel findings indicated that PCAD increases pericyte coverage and alleviates pericyte damage to improve the stability of atherosclerotic plaques, which is accomplished by regulating TGF-β1/TGFBR1/Smad2/3 signaling in pericytes.

Serum ANGPTL4 and SIRT1 factor levels and the Carotid Atherosclerotic plaque stability relationship analysis.

This study was to investigate the relationship between the levels of Angiopoietin-Like Protein 4 (ANGPTL4) and Silent Mating-type Information Regulation 2 Homolog 1 (SIRT1) and the stability of carotid atherosclerotic plaque. For this purpose, 108 patients with coronary heart disease in our hospital from Jan 2021 to May 2022 were selected as the coronary heart disease (CHD) group and 80 patients with the healthy examination as the control group. Patients' serum levels of ANGPTL4 and SIRT1 were collected, and their stability of carotid atherosclerotic plaque was determined by carotid ultrasound. According to their stability results, patients were divided into three subgroups: No plaque, Stable plaque, and Unstable plaque. The serum ANGPTL4 and SIRT1 levels were analyzed in different groups, and the correlation between their serum levels and the stability of carotid atherosclerotic plaque was analyzed by rank correlation. Results showed that the CHD group's serum ANGPTL4 and SIRT1 levels were lower, with statistical significance (P<0.05); A statistically significant difference in serum ANGPTL4 and SIRT1 levels were observed among patients with No plaques, Stable plaques, and Unstable plaques (P<0.05); A negative correlation was observed between serum levels of ANGPTL4 and SIRT1 and the stability of carotid atherosclerotic plaque (r=-0.438, -0.717, P<0.001); Serum ANGPTL4 and SIRT1 can be used as the evaluation method of carotid atherosclerotic plaque stability. When ANGPTL4 ≤ 30.17mg/L and SIRT1 ≤ 6.91μg/L, patients were more likely to develop unstable plaques; When ANGPTL4 ≤ 30.40mg/L and SIRT1 ≤ 6.87μg/L, patients were more likely to develop plaques (instability and/or stability). In conclusion, the serum levels of ANGPTL4 and SIRT1 in patients with CHD decreased. ANGPTL4 and SIRT1 will participate in the formation and development of carotid plaque, which can be used as a serological evaluation index to evaluate the occurrence and carotid atherosclerotic plaque's stability.

Role of Ayurveda, Lifestyle Modification, and Panchakarma Therapy on Stabilization of Atherosclerotic Plaque in Known Coronary Artery Disease Patient

Atherosclerois is a major health concern in India and imposes a significant burden on the population. The prevalence of risk factors such as hypertension, obesity, smoking and high cholesterol levels contribute to the rising incidence of atherosclerosis in the country. A 57-year-old male presented with primary complaints of chest pain and heaviness, left arm pain, upper back pain, jaw pain, dyspnea on exertion grade I, flatulence, gaseous distension, cervical pain, scapular region pain, shoulder pain, constipation, and insomnia. He also complained of postprandial angina New York Heart Association (NYHA) Class III. The patient was a photographer by profession and had a history of hypertension, diabetes mellitus, and coronary artery disease. On 29th February 2020, he underwent computed tomography (CT) coronary angiography at another clinic which revealed stenosis of the 3 main coronary arteries – more than 90% stenosis in mid left anterior descending artery (LAD), 80–90% stenosis in proximal left circumflex artery (LCx), and 80–90% stenosis in proximal right coronary artery (RCA). The patient was advised an Ayurveda-based low-carbohydrate high antioxidant diet of 1,000 calories daily for the first 12 weeks. This case report supports the relationship between an Ayurveda-based low-carbohydrate high antioxidant diet and atheroma regression in a high-risk coronary artery disease patient.

Sulfated glucuronomannan hexamer inhibits lipid accumulation and ameliorates atherosclerosis in apolipoprotein E-deficient mice

Atherosclerosis (AS) is the leading cause of cardiovascular diseases worldwide, which generates huge health and economic burdens on humanity. The anti-atherosclerosis activities of glucuronomannan oligosaccharides (Gs) and sulphated glucuronomannan oligosaccharides (SGs) were investigated in vitro and in vivo. Among these Gs and SGs, G6S1 (higher sulphated glucuronomannan hexamer) decreased the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), then down-regulated NF-κB signaling pathway to reduce the release of TNF-α and IL-1β, and targeted PI3K/Akt/mTOR signaling pathway to enhance autophagy in a dose-dependent manner, which showed the best anti-atherosclerosis activity. Moreover, data showed that G6S1 improves liver function, reduced the progression and promoted the stabilization of atherosclerotic plaques, and also decreases LOX-1 expression in plaque macrophages in ApoE-/- mice. In summary, our data indicated that sulfated glucuronomannan hexamer exhibited the anti-atherosclerosis through down-regulating LOX-1 in macrophages, and the degree of polymerization and sulphation had essential roles in anti-atherosclerosis bioactivity of oligosaccharides.

The Effect of PCSK9 Inhibition on the Stabilization of Atherosclerotic Plaque Determined by Biochemical and Diagnostic Imaging Methods.

Atherosclerosis is a multifactorial, progressive, chronic inflammatory disease. Ultrasound and magnetic resonance imaging are the most accurate predictors of atherosclerotic plaque instability (MRI). Cytokines such as osteopontin, osteoprotegerin, and metalloproteinase 9 could be used as the most recent markers to identify and track the efficacy of anti-atherosclerotic therapy. Patients with USG and MRI-verified unstable atherosclerotic plaque were included in the study. Biomarker concentrations were measured and compared before and after PCSK9 inhibitor therapy. Additionally, concentrations prior to treatment were correlated with MRI images of the carotid artery. After treatment with alirocumab, the concentrations of MMP-9 (p < 0.01) and OPN, OPG (p < 0.05) decreased significantly. Furthermore, the results of OPN, OPG, and MMP 9 varied significantly depending on the type of atherosclerotic plaque in the MRI assay. In stable atherosclerotic plaques, the concentrations of OPN and OPG were greater (p < 0.01), whereas the concentration of MMP9 correlated with the instability of the plaque (p < 0.05). We demonstrated, probably for the first time, that alirocumab therapy significantly decreased the serum concentration of atherosclerotic plaque markers. In addition, we demonstrated the relationship between the type of atherosclerotic plaque as determined by carotid MRI and the concentration of these markers.

The effect of PCSK9 inhibition on the stabilization of atherosclerotic plaque determined by biochemical and diagnostic imaging methods

The effect of PCSK9 inhibition on the stabilization of atherosclerotic plaque determined by biochemical and diagnostic imaging methods

Comparison of ultrasound techniques in assessment atherosclerotic plaque stability in the carotid arteries

Comparison of ultrasound techniques in assessment atherosclerotic plaque stability in the carotid arteries

Combining idebenone and rosuvastatin prevents atherosclerosis by suppressing oxidative stress and NLRP3 inflammasome activation

Atherosclerosis is a progressive inflammatory disease activated by excessive oxidized low-density lipoprotein (ox-LDL). Statins are the first-line choice to reduce the risk of cardiovascular disease. However, statin-associated side effects prompt dose reduction or discontinuation. Idebenone could protect against atherosclerosis by scavenging reactive oxygen species (ROS). Although both idebenone and statins have certain efficacy, neither of them can achieve a completely satisfactory effect. Here, we aim to investigate the anti-atherosclerotic effect of the combination of idebenone and statins. Apolipoprotein E knockout (ApoE−/−) mice were given idebenone (400 mg/kg/d), rosuvastatin (10 mg/kg/d) or a combination of idebenone and rosuvastatin. Histological and immunohistochemical staining were used to analyze the size and composition of the plaque. In vivo and in vitro experiments were conducted to explore the possible mechanism. Idebenone and rosuvastatin both reduced plaque burden and increased the stability of atherosclerotic plaques in the ApoE−/− mice. Mice receiving the combination therapy had even reduced and more stable atherosclerotic plaques than mice treated with idebenone or rosuvastatin alone. NLRP3 and IL-1β were further downregulated in mice receiving combination therapy compared with mice treated with monotherapy. The combination treatment also markedly reduced oxidative stress and cell apoptosis in vivo and in vitro. In conclusion, our data demonstrate that the combination of idebenone and rosuvastatin works synergistically to inhibit atherosclerosis, and that the use of both substances together is more effective than using either substance alone. From a therapeutic point, combining idebenone and rosuvastatin appears to be a promising strategy to further prevent atherosclerosis.

LncRNAs as Regulators of Atherosclerotic Plaque Stability.

Current clinical data show that, despite constant efforts to develop novel therapies and clinical approaches, atherosclerotic cardiovascular diseases (ASCVD) are still one of the leading causes of death worldwide. Advanced and unstable atherosclerotic plaques most often trigger acute coronary events that can lead to fatal outcomes. However, despite the fact that different plaque phenotypes may require different treatments, current approaches to prognosis, diagnosis, and classification of acute coronary syndrome do not consider the diversity of plaque phenotypes. Long non-coding RNAs (lncRNAs) represent an important class of molecules that are implicated in epigenetic control of numerous cellular processes. Here we review the latest knowledge about lncRNAs' influence on plaque development and stability through regulation of immune response, lipid metabolism, extracellular matrix remodelling, endothelial cell function, and vascular smooth muscle function, with special emphasis on pro-atherogenic and anti-atherogenic lncRNA functions. In addition, we present current challenges in the research of lncRNAs' role in atherosclerosis and translation of the findings from animal models to humans. Finally, we present the directions for future lncRNA-oriented research, which may ultimately result in patient-oriented therapeutic strategies for ASCVD.

Haemodynamic Effects on the Development and Stability of Atherosclerotic Plaques in Arterial Blood Vessel.

Studying the formation and stability of atherosclerotic plaques in the hemodynamic field is essential for understanding the growth mechanism and preventive treatment of atherosclerotic plaques. In this paper, based on a multiplayer porous wall model, we established a two-way fluid-solidinteraction with time-varyinginlet flow. The lipid-rich necrotic core (LRNC) and stress in atherosclerotic plaque were described for analyzing the stability of atherosclerotic plaques during the plaque growth by solving advection-diffusion-reaction equations with finite-element method. It was found that LRNC appeared when the lipid levels of apoptotic materials (such as macrophages, foam cells) in the plaque reacheda specified lowerconcentration, and increased with the plaque growth. LRNC was positively correlated with the blood pressure and was negatively correlated with the blood flow velocity. The maximum stress wasmainlylocatedat the necrotic core and graduallymovedtoward the left shoulder of the plaque with the plaque growth, which increases the plaque instability and the risk of the plaque shedding. The computational model may contribute to understanding the mechanisms of early atherosclerotic plaque growth and the risk of instability in the plaque growth.

Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability

Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE−/− and Ldlr−/− experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.

Macrophage death in atherosclerosis: potential role in calcification.

Cell death is an important aspect of atherosclerotic plaque development. Insufficient efferocytosis of death cells by phagocytic macrophages leads to the buildup of a necrotic core that impacts stability of the plaque. Furthermore, in the presence of calcium and phosphate, apoptotic bodies resulting from death cells can act as nucleation sites for the formation of calcium phosphate crystals, mostly in the form of hydroxyapatite, which leads to calcification of the atherosclerotic plaque, further impacting plaque stability. Excessive uptake of cholesterol-loaded oxidized LDL particles by macrophages present in atherosclerotic plaques leads to foam cell formation, which not only reduces their efferocytosis capacity, but also can induce apoptosis in these cells. The resulting apoptotic bodies can contribute to calcification of the atherosclerotic plaque. Moreover, other forms of macrophage cell death, such as pyroptosis, necroptosis, parthanatos, and ferroptosis can also contribute by similar mechanisms to plaque calcification. This review focuses on macrophage death in atherosclerosis, and its potential role in calcification. Reducing macrophage cell death and/or increasing their efferocytosis capacity could be a novel therapeutic strategy to reduce the formation of a necrotic core and calcification and thereby improving atherosclerotic plaque stability.

Plaque Macrophage‐Targeting Nanosystems with Cooperative Co‐Regulation of ROS and TRAF6 for Stabilization of Atherosclerotic Plaques (Adv. Funct. Mater. 28/2023)

Plaque Macrophage‐Targeting Nanosystems with Cooperative Co‐Regulation of ROS and TRAF6 for Stabilization of Atherosclerotic Plaques (Adv. Funct. Mater. 28/2023)