Atherosclerotic Plaque Formation Research Articles

Increased caveolin 1 by human antigen R exacerbates Porphyromonas gingivali-induced atherosclerosis by modulating oxidative stress and inflammatory responses

Objective: Many different types of infectious oral diseases have been identified clinically, including chronic periodontitis. Porphyromonas gingivalis is the main pathogen causing chronic periodontitis, which is closely related to atherosclerosis (AS) and can promote the expression levels of caveolin 1 (Cav-1) and induced ribonucleic acid (RNA)-binding protein human antigen R (HuR). However, the roles of Cav-1 and its relationship with HuR in P. gingivalis-mediated AS progression remain largely unknown. Here, we aimed to detect the role and molecular mechanisms of Cav-1 in P. gingivalis-mediated AS. Material and Methods: To investigate the role of Cav-1 in P. gingivalis-mediated AS, we infected human umbilical vein endothelial cells (HUVECs) with P. gingivalis at a multiplicity of infection of 100:1 for 6, 12, and 24 h to simulate P. gingivalis-induced AS models in vitro and then transfected them with Cav-1 small interfering RNA to silence Cav-1. Combining molecular biology experimental techniques such as cell counting kit-8 assay, enzyme-linked immunosorbent assay, immunofluorescence staining, flow cytometry, Western blotting, and Oil Red O staining, and apolipoprotein E-deficient AS model mice, the impacts of Cav-1 on cell viability, inflammation, oxidative stress, apoptosis, Cav-1 and intercellular cell adhesion molecule-1 (ICAM-1) levels, and atherosclerotic plaque formation were investigated. Then, the relationship between Cav-1 and HuR was investigated through biotin pull-down and RNA immunoprecipitation assays, reverse transcription quantitative polymerase chain reaction, and Western blot. Results: P. gingivalis can induce Cav-1 expression in a time- and dose-dependent manner (P < 0.05). This effect can inhibit the proliferation of HUVECs (P < 0.05). Cav-1 interference repressed inflammatory response, reactive oxygen species (ROS) and ICAM-1 levels, and apoptosis in the HUVECs (P < 0.05). Cav-1 messenger RNA was stabilized by HuR, which can bind to the 3’ untranslated region of Cav-1. Increase in HuR level reversed the effects of Cav-1 silencing on ROS and ICAM-1 levels and apoptosis in the HUVECs (P < 0.05). In addition, the levels of inflammatory response, oxidative stress, and atherosclerotic plaque formation induced by P. gingivalis in the mouse model were significantly reduced after Cav-1 expression was inhibited (P < 0.05). Conclusion: HuR-activated Cav-1 may promote atherosclerotic plaque formation by modulating inflammatory response and oxidative stress, leading to AS.

Sodium Danshensu Inhibits Macrophage Inflammation in Atherosclerosis via the miR-200a-3p/MEKK3/NF-κB Signaling Pathway.

Macrophages are fundamental cellular components of atherosclerotic plaques, and inhibition of macrophage inflammation can delay the development of atherosclerotic plaques. Sodium danshensu (SDSS) can inhibit inflammatory responses and thus delay atherosclerosis, but the specific mechanism remains unclear.The effect of SDSS in inhibiting atherosclerosis was confirmed by observing and detecting atherosclerotic plaque area, morphology and lipid levels in the aorta. The mechanism by which SDSS attenuated atherosclerotic plaques was elucidated by in vivo and in vitro detection of inflammation-related mRNA and protein expression. In addition, bioinformatics analysis, RT-qPCR and dual-luciferase assays were used to predict and validate the potential miRNAs of SDSS to attenuate atherosclerosis. miR-200a-2p mimic and inhibitor were then compared for their effects on the efficacy of SDSS.SDSS inhibited atherosclerotic plaque formation and suppressed the expression of MEKK3, TNF-α, and IL-1β as well as nuclear factor-κB (NF-κB) phosphorylation and nuclear translocation to attenuate inflammatory responses. Bioinformatic predictions combined with RT-qPCR results and dual-luciferase assays indicated that miR-200a-3p negatively regulated MEKK3 expression by directly targeting the 3'UTR region of MEKK3, thereby blocking MEKK3. Further studies showed that miR-200a-3p inhibitor, but not miR-200a-3p mimic, reversed the beneficial effects of SDSS on inflammation.SDSS inhibited macrophage inflammation by modulating the miR-200a-3p/MEKK3/NF-κB signaling pathway.

THE IMPACT OF EXOGENOUS AND ENDOGENOUS FACTORS ON VASCULAR WALL ELASTICITY AND POTENTIAL CLINICAL EFFECTS (Review Article)

Vascular aging is associated with profound changes in the structural properties of the arterial wall. Arterial hypertension, diabetes mellitus, and chronic kidney disease are the primary determinants of the loss of elasticity and reduced compliance of the vascular wall. Arterial stiffness is a key parameter for assessing the elasticity of the arterial wall and can be easily evaluated using non-invasive methods such as pulse wave velocity. Early assessment of arterial stiffness is critical, as its changes may precede the clinical manifestations of cardiovascular disease. With age, arterial walls become stiffer, leading to an increase in systolic blood pressure and an increased risk of cardiovascular events such as stroke, myocardial infarction, or heart failure. The gradual decrease in vascular elasticity is accompanied by remodeling of their structure, an increase in collagen fibers, and a decrease in elastin, which exacerbates the problem. In addition, the mechanical stress on the vascular wall, which increases with age, worsens its condition, provoking the formation of atherosclerotic plaques. Arterial stiffness, as an important biomarker of vascular aging, is also an indicator of increased cardiovascular risk, independent of other factors such as blood pressure or the presence of comorbidities. Therefore, timely diagnosis of arterial stiffness can help prevent serious complications and adjust treatment for patients at risk. Important are also preventive measures, including a healthy lifestyle, physical activity, and control of the underlying diseases that contribute to the acceleration of vascular aging processes. Moreover, the influence of endogenous and exogenous factors, such as diet, the presence of chronic diseases, and bad habits (in particular, smoking), contribute to the acceleration of these processes. Innovative diagnostic methods, such as magnetic resonance imaging (MRI) or ultrasound, allow detecting these changes at early stages and, accordingly, adapting treatment.

Vascular Extracellular Matrix in Atherosclerosis

The extracellular matrix (ECM) plays a central role in the structural integrity and functionality of the cardiovascular system. Moreover, the ECM is involved in atherosclerotic plaque formation and stability. In fact, ECM remodeling affects plaque stability, cellular migration, and inflammatory responses. Collagens, fibronectin, laminin, elastin, and proteoglycans are crucial proteins during atherosclerosis development. This dynamic remodeling is driven by proteolytic enzymes such as matrix metalloproteinases (MMPs), cathepsins, and serine proteases. Exploring and investigating ECM dynamics is an important step to designing innovative therapeutic strategies targeting ECM remodeling mechanisms, thus offering significant advantages in the management of cardiovascular diseases. This review illustrates the structure and role of vascular ECM, presenting a new perspective on ECM remodeling and its potential as a therapeutic target in atherosclerosis treatments.

Piezo1-mediated mechanotransduction enhances macrophage oxidized low-density lipoprotein uptake and atherogenesis.

Macrophages in the vascular wall ingest and clear lipids, but abundant lipid accumulation leads to foam cell formation and atherosclerosis, a pathological condition often characterized by tissue stiffening. While the role of biochemical stimuli in the modulation of macrophage function is well studied, the role of biophysical cues and the molecules involved in mechanosensation are less well understood. Here, we use genetic and pharmacological tools to show extracellular oxidized low-density lipoproteins (oxLDLs) stimulate Ca2+ signaling through activation of the mechanically gated ion channel Piezo1. Moreover, macrophage Piezo1 expression is critical in the transduction of environmental stiffness and channel deletion suppresses, whereas a gain-of-function mutation exacerbates oxLDL uptake. Additionally, we find that depletion of myeloid Piezo1 protects from atherosclerotic plaque formation in vivo. Together, our study highlights an important role for Piezo1 and its respective mutations in macrophage mechanosensing, lipid uptake, and cardiovascular disease.

C-C motif chemokine ligand 3 is associated with atherosclerotic plaque vulnerability and increased risk of mortality

Abstract Background and Purpose Chemokines play a crucial role in the inflammatory process underlying atherosclerotic plaque formation, progression and subsequent cardiovascular events. However, the specific role of C-C motif chemokine ligand 3 (CCL3) in atherosclerosis remains largely unexplored. This study aims to explore associations between intra-plaque levels of CCL3 and plaque vulnerability as well as to investigate the prognostic role of circulating CCL3 levels in patients undergoing carotid endarterectomy. Methods The CCL3 protein expression was measured using a proximity extension assay in 207 human carotid plaques and 558 plasma samples from patients undergoing carotid endarterectomy, all enrolled in the Carotid Plaque Imaging Project (CPIP) cohort. Protein expression is quantified as normalized protein expression (NPX), an arbitrary unit on a log2-scale. Plaque components and extracellular matrix including smooth muscle cells, macrophages, neutral lipids, intraplaque hemorrhage, collagen (by histology), and matrix metalloproteinases (assessed biochemically), were quantified. Plaque vulnerability index was calculated as the sum percentage of plaque areas stained for lipids, macrophages and hemorrhage, divided by the sum percentage of smooth muscle cells and collagen. Patients were followed up to 10.2 years to record cardiovascular events and mortality. Results Plaque and circulating levels of CCL3 were higher in symptomatic patients compared to asymptomatic patients (plaque, median NPX (interquartile range, IQR): 18.2 (17.4–19.1) vs 17.2 (16.4–18.0), P<0.001; plasma, median NPX (IQR): 1.78 (1.42–2.21) vs 1.56 (1.28–1.97), P<0.001). Plaque levels of CCL3 showed positive correlations with neutral lipids, macrophages, intraplaque hemorrhage, plaque vulnerability index and matrix metalloproteinases including MMP1, MMP2, MMP9, MMP10 and TIMP1, but inversely with smooth muscle cells. Among 511 patients with complete follow-up and circulating CCL3 measures, 144 (28.2%) patients developed cardiovascular events and 123 (24.1%) patients died. Elevated circulating CCL3 levels were associated with increased risk of cardiovascular events (hazard ratio (HR) per standard deviation (SD) = 1.40, 95% CI 1.06–1.84) and mortality (HR per SD=1.77, 95% CI 1.34–2.33), respectively. Higher levels of circulating CCL3 remained independently associated with an increased risk of mortality (HR per SD=1.50, 95% CI 1.09–2.04) even after adjustment for potential confounders. Conclusions Plaque levels of CCL3 are associated with plaque vulnerability features. Circulating levels of CCL3 predict higher risk of cardiovascular events and mortality among carotid endarterectomy patients.

Immunohistochemical Localization of Fibroblast Activation Protein in Coronary Arteries with Different Forms of Atherosclerosis

Background: Fibroblast activation protein (FAP) is a cell surface glycoprotein expressed by myofibroblasts in areas of active tissue remodeling. It plays a potentially important role in cardiac remodeling, atherosclerotic plaque formation, and plaque rupture. Given the distinct pathophysiology and morphology of different forms of atherosclerosis, we analyzed FAP expression in human coronary vessels with no coronary artery disease, atherosclerotic plaques at different levels of progression, and other distinct forms of coronary disease in post bypass vein grafting and cardiac allograft vasculopathy after a heart transplant. Methods: Immunohistochemical staining with monoclonal F19 mouse anti-human FAP antibody was performed to identify FAP in human atherosclerotic plaques, coronary bypass atherosclerosis, and post-transplant arteriosclerosis. The presence and distribution of FAP in different types and stages of human atherosclerosis were compared. Results: There was no FAP staining in patients with no significant coronary disease. All different types of human atherosclerotic lesioning lesions showed the presence of FAP expression, with different staining patterns in advanced atherosclerotic plaque, vein graft atherosclerosis lesions, and arteriosclerosis after a heart transplant. Conclusions: These data suggest that FAP may be a potential diagnostic marker and target for interventions, not only in coronary atherosclerotic plaque, but also in other forms of coronary disease, which have distinct pathophysiologies and currently limited treatment options.

Beyond the plaque: immunological implications of risk factors in atherosclerosis

The formation of atherosclerotic plaque results from the complex interaction between modifiable and non-modifiable risk factors, through immune mechanisms that orchestrate both inflammatory and anti-inflammatory processes. Atherosclerosis often culminates in ischemic heart disease or cerebrovascular events, which are the leading causes of mortality worldwide. Currently, primary prevention focuses on controlling modifiable risk factors. Therefore, understanding the molecular mechanisms underlying the damage induced by these risk factors is essential to develop more effective treatments. This article provides a detailed review of the immunological processes underlying the initiation and progression of atheroma plaque, exploring their relationship with traditional risk factor such as smoking, diabetes mellitus, dyslipidemia, and hypertension, as well as a new potential risk factor: microbiota dysbiosis. Furthermore, the attributable risk of each factor is independently assessed, and the effectiveness of risk factor control measures is demonstrated as the best strategy to date for the regression of atherosclerosis and the prevention of its complications.

A Retrospective Observational Study Examining Physical Activity Among Adults in the United States With Angina or Coronary Heart Disease.

Coronary heart disease (CHD) involves inadequate blood supply to the myocardium by the coronary arteries due to the formation of atherosclerotic plaque in the vessel lumen. It has a complex etiopathogenesis. Physical activity (PA) and exercise lead to vascular remodeling and improved endothelial function, which, in turn, improves the arterial blood supply to the myocardium. The study aims to determine the prevalence of self-reported PA among CHD patients in the United States based on demographic, socioeconomic, and healthcare access variables for the year 2021. The data for the study on CHD were extracted using the Behavioral Risk Factor Surveillance System (BRFSS) Web-Enabled Analysis Tool database of the U.S. The control variables used broadly include demographics, socioeconomic, and healthcare access. In 2021, 433,615 people in the USA participated in the BRFSS study. Among them, 22,819 self-identified as having angina or CHD. In the past month, 62.2% of participants with the disease were involved in PA, and 37.8% were not. Among participants without angina or CHD, 76.5% were involved, and 23.5% were not involved in PA in the past month. This study highlights the need for specific interventions to overcome obstacles preventing PA among CHD patients.

Contribution of the arterial cells to atherosclerosis and plaque formation.

Atherosclerosis is commonly known as an inflammatory disease that is characterized by lipid deposition in the arterial wall, causing gradual restriction or complete blockade of blood flow, which can cause complications such as myocardial infarction, stroke, or peripheral artery disease. Several factors contribute to initiation and progression of atherosclerotic plaque formation. The role of macrophages and leukocytes in atherosclerosis has been well explored. Here, we provide an overview of what has been reported on the role and impact of the arterial cells on plaque formation, and vice versa. The atherogenic environment can trigger transformation and dedifferentiation of the endothelial cells (ECs), smooth muscle cells, and fibroblasts (FBs) whereby they can either directly contribute to plaque formation or influence its composition. Recent studies have demonstrated the plasticity in the identity of the arterial cells, the formation of intermediate cell types that share the characteristics of multiple cell types, and have revealed novel roles and functions for these cells in atherosclerosis. The potential for all vascular cells to cross-transdifferentiate, and detection of cells with mosaic characteristics in the atherosclerotic plaques reveal that the plaque environment is a complex and dynamic environment that could regulate the disease progression independent from the circulating lipid levels. We will also provide an overview on the interplay between sex and atherosclerosis, which has remained an underexplored area.

The role of biomarkers on hemodynamics in atherosclerotic artery

Atherosclerosis, a chronic inflammatory cardiovascular disease, leads to arterial constriction caused by the accumulation of lipids, cholesterol, and various substances within artery walls. Such plaque can rupture, resulting in a blood clot that obstructs major arteries and may initiate myocardial infarction, ischemic stroke, etc. Atherosclerotic plaque formation begins with the accumulation of foam cells and macrophages within the intima layer of the arterial wall. At the latter stage, the smooth muscle cells migrated from deeper artery wall layers, contributing to the fibrous cap formation and plaque stabilizing. A developed plaque gradually enters the lumen and narrows down the lumen to impede blood flow. We introduce a two-phase and macroscopic model to investigate the progression of plaque growth in its advanced stage and analyze the minimum gap (Lumen Clearance) within an atherosclerotic artery so that blood cells can pass through. Cardiac troponin, a high specificity and sensitivity biomarker, facilitates early detection of elevated myocardial infarction, ischemic stroke risks, etc. This study aims at establishing a relationship between the troponin concentration in atherosclerotic arteries and their internal clearance, which could significantly improve our understanding of disease progression. Our observations show that the plaque undergoes rapid evolution in its initial stages, gradually slowing down over time to reach a stable state. A positive correlation exists between the maximum plaque depth and cardiac troponin concentration in the blood. However, the lumen clearance exhibits the opposite behavior. The speed of blood cells slows down at an enhanced plaque depth within atherosclerotic arteries.

Neutrophil count as a risk factor for cardiovascular diseases: how can we manage it?

Neutrophils activation plays a pivotal role in the pathogenesis of atherosclerotic plaque formation, progression and rupture. An association between the leukocyte count and the risk of developing myocardial infarction has been well known for many years; however, only recently did Mendelian randomization studies show that a high neutrophil count is a causal risk factor for atherosclerotic cardiovascular disease. On the other hand, experimental studies show that depletion of circulating neutrophils impairs plaque development. Clopidogrel, an antiplatelet agent, is widely used in combination with aspirin to reduce the incidence of ischemic events in patients treated with coronary stenting. Chronic treatment with this drug reduces inflammatory markers and neutrophil numbers, rarely causing severe leukopenia. The purpose of this review is to present recent evidence showing the link between neutrophil number and the development of cardiovascular diseases and to discuss how the clopidogrel-induced reduction in the neutrophil count may be a beneficial off-target effect of this drug.

Siglec-5 as a novel receptor mediates endothelial cells oxLDL transcytosis to promote atherosclerosis

BackgroundExcessive subendothelial retention of oxidized low-density lipoprotein (oxLDL) and subsequent oxLDL engulfment by macrophages leads to the formation of foam cells and the development of atherosclerosis. Our previous study showed that the plasma level of sialic acid-binding immunoglobulin-like lectin 5 (Siglec-5) was a novel biomarker for the prognosis of atherosclerosis in diabetic patients. However, the role and underlying mechanisms of Siglec-5 in atherosclerosis have not been elucidated. MethodsThe interaction between oxLDL and Siglec-5 was detected by fluorescence colocalization and coimmunoprecipitation. The effect of oxLDL on Siglec-5 expression was detected in endothelial cells and macrophages, and the effect of Siglec-5 on oxLDL transcytosis and uptake was investigated. Siglec-5 was overexpressed in mice using recombinant adeno-associated virus vector serotype 9 (rAAV9-Siglec-5) to evaluate the effect of Siglec-5 on oxLDL uptake and atherogenesis in vivo. In addition, the effects of Siglec-5 antibodies and soluble Siglec-5 proteins on oxLDL transcytosis and uptake and their role in atherogenesis were investigated in vivo and in vitro. ResultsWe found that oxLDL interacted with Siglec-5 and that oxLDL stimulated the expression of Siglec-5. Siglec-5 promotes the transcytosis and uptake of oxLDL, while both anti-Siglec-5 antibodies and soluble Siglec-5 protein attenuated oxLDL transcytosis and uptake. Interestingly, overexpression of Siglec-5 by recombinant adeno-associated viral vector serotype 9 (rAAV9-Siglec-5) promoted the retention of oxLDL in the aorta of C57BL/6 mice. Moreover, overexpression of Siglec-5 significantly accelerated the formation of atherosclerotic lesions in Apoe−/− mice. Moreover, both anti-Siglec-5 antibodies and soluble Siglec-5 protein significantly alleviated the retention of oxLDL in the aorta of rAAV9-Siglec-5-transfected C57BL/6 mice and the formation of atherosclerotic plaques in rAAV9-Siglec-5-transfected Apoe−/− mice. ConclusionOur results suggested that Siglec-5 was a novel receptor that mediated oxLDL transcytosis and promoted the formation of foam cells. Interventions that inhibit the interaction between oxLDL and Siglec-5, including anti-Siglec-5 antibody or soluble Siglec-5 protein treatment, may provide novel therapeutic strategies in treating atherosclerosis.

Modeling the processes of transendothelial transport of LDL and macrophage migration

Atherosclerosis is a multifactorial process involving various pathological mechanisms: inflammation, lipoprotein modification, cholesterol accumulation, endothelial dysfunction, oxidative stress and formation of atherosclerotic plaque. The main participants in the development of this disease are endothelial cells, leukocytes and smooth muscle cells of intima. The adult endothelium contains heterogeneous cells, including typical endothelial cells (TEC) and giant multinucleated EC variants (MVEC). The process of passing molecules is called transendothelial transport (TET). The purpose of this work is to model the processes of TET of low-density lipoproteins (LDL) and monocyte migration using various EC variants. In the study, a human EC line (EA.hy926) was used. Multicore variants of EC (MVEC) were obtained by treating EC with a 50% solution of polyethylene glycol 6000. To study LDL transcytosis and monocyte migration, tablets with inserts (0.4 or 3.0 micron pore diameter, respectively) forming a two-level system were used. The LDL transmission rate was assessed by measuring the amount of cholesterol in the upper and lower chambers every 2, 5 and 24 hours. A modified Folch method was used to measure the amount of cholesterol. The cholesterol content was adjusted according to the total protein level in the well, measured by the Lowry method. The migration of macrophages was estimated by direct counting of cells. The content of internalized cholesterol in the MVEC was statistically significantly higher than in the EC. The rate of LDL transport did not differ. The rate of passage of the endothelial barrier formed by MVEC by macrophages was higher at points 2 and 5 hours. After 24 hours the number of migrated cells did not differ. The rate of transendothelial transport for typical and multinucleated variants of EC did not statistically differ. Although the presence of MBEC does not affect the transport of lipoproteins into the subendothelial layer, the fact that multinucleated cells accumulate lipid droplets more actively than typical ECS may indicate an important role in the pathogenesis of atherosclerosis. The rate of macrophage migration after 2 and 5 hours was higher for MVEC than for TEC, whereas immature macrophages did not migrate through the endothelial barrier for 24 hours.

Implications for Clinical Practice, Mechanisms, and Efficacy of Ageratum conyzoides Leaf Extracts in Streptozotocin-Induced Diabetes Rats: An Investigation into Their Antidiabetic, Hypolipidemic, and Antiatherogenic Activities

Ageratum conyzoides, a perennial herb native to tropical and subtropical regions, has been utilized in traditional medicine for centuries due to its diverse therapeutic properties. This review consolidates current research on the antidiabetic, hypolipidemic, and antiatherogenic effects of Ageratum conyzoides leaf extracts, specifically in streptozotocin-induced diabetic rat models. The review explores the plant’s potential mechanisms of action, including enhancement of insulin sensitivity, improvement of lipid profiles, and reduction of atherosclerotic plaque formation. Ageratum conyzoides extracts have demonstrated significant antidiabetic effects by lowering blood glucose levels, enhancing insulin secretion, and improving insulin sensitivity. They also exhibit hypolipidemic effects by reducing total cholesterol, LDL cholesterol, and triglycerides, while increasing HDL cholesterol. Additionally, these extracts show antiatherogenic properties by inhibiting plaque formation and reducing oxidative stress, thereby supporting cardiovascular health. The review examines the pharmacokinetics and bioavailability of Ageratum conyzoides bioactive compounds, emphasizing the need for further research to optimize their therapeutic potential. Comparative studies highlight its efficacy relative to other natural remedies and pharmaceuticals, noting its favorable safety profile. The review underscores the importance of integrating Ageratum conyzoides into both traditional and modern medicine practices and explores its role in dietary supplements and functional foods. Ongoing translational research and clinical trials are essential to validate the efficacy and safety of these extracts for broader clinical application. Keywords: Ageratum conyzoides, Leaf Extracts, Streptozotocin, Diabetes, Rats

CTRP9: An Anti-Atherosclerotic Factor in ApoE Knockout Mice through Oxidative Stress Inhibition

Background: C1q/tumor necrosis factor-related protein-9 (CTRP9) is critically involved in the pathophysiology of metabolic and cardiovascular disorders. This investigation aimed to clarify the mechanism underlying the role of CTRP9 in atherosclerosis in apolipoprotein E (ApoE) knockout (KO) mice. Methods: ApoE KO mice were fed a Western diet and injected with a virus which resulted in CTRP9 overexpression or knockdown for 12 weeks. The plasma lipid levels and atherosclerotic plaque areas were measured after the mice were euthanized. Aortas were isolated, and RNA sequencing was performed to identify the differentially expressed genes and related signaling pathways. Finally, plasma oxidative stress factors were measured to demonstrate the reliability of the RNA sequencing results. Results: The plasma lipid levels in the CTRP9 overexpression group did not significantly differ from those in the green fluorescence protein (GFP) group. Markablely, CTRP9 overexpression inhibited atherosclerotic plaque formation in ApoE KO mice, whereas CTRP9 knockdown promoted plaque formation. RNA sequencing analysis identified 3485 differentially expressed genes that were prominently enriched across 55 signaling pathways. Additionally, plasma oxidative stress factors were significantly reduced after CTRP9 overexpression, whereas these factors were increased after CTRP9 knockdown, which was consistent with the results of the RNA sequencing analysis. Conclusions: These findings demonstrated that CTRP9 alleviated inflammation and cholesterol metabolism, which reduced oxidative stress in an atherosclerotic animal model. These beneficial effects may mediate the suppression of lesion development in the aorta.

Apolipoprotein B-48 and late graft failure in kidney transplant recipients.

Transplant vasculopathy resembles atherosclerotic plaque formation and is a major contributor to late graft failure in kidney transplant recipients (KTR). Remnant lipoproteins and associated triglycerides are causal risk factors for atherosclerotic plaques and have been implicated in late kidney graft failure. However, whether remnants derived from liver (containing apolipoprotein [apo] B100) or intestine (containing apoB48) are clinically more important is unclear. The current study investigated the association between baseline fasting apoB48 levels and late kidney graft failure. 481 KTR with a functioning graft for at least 1 year were included in this retrospective, observational longitudinal single center cohort study. The primary endpoint was death-censored late graft failure, defined as need for initiation of dialysis or re-transplantation. ApoB48 was measured by enzyme-linked immunosorbent assay. During a median follow-up of 9.5 years, 61 KTR developed graft failure (12.7%). At baseline, KTR with higher apoB48 levels had lower eGFR (P<.001), lower high-density lipoprotein (HDL) cholesterol (P<.001), increased triglycerides (P<.001) and used cyclosporine more frequently (P=.003). Cox regression showed that higher baseline apoB48 was associated with higher risk of late graft failure [hazard ratio (95% confidence interval), 1.59 (1.22, 2.07), P<.001], independent of stepwise adjustment for potential confounders, including age and sex, immunosuppression type and proteinuria, triglycerides, and waist circumference (fully adjusted HR, 1.78 (1.29, 2.47), P<.001]. ApoB48 is strongly associated with late graft failure, independent of potential confounders. Since apoB48-containing lipoproteins originate from the intestine, this study provides a rationale for considering pharmacological interventions targeting lipid absorption to improve graft outcome.

Wall Shear Stress (WSS) Analysis in Atherosclerosis in Partial Ligated Apolipoprotein E Knockout Mouse Model through Computational Fluid Dynamics (CFD).

Atherosclerosis involves an inflammatory response due to plaque formation within the arteries, which can lead to ischemic stroke and heart disease. It is one of the leading causes of death worldwide, with various contributing factors such as hyperlipidemia, hypertension, obesity, diabetes, and smoking. Wall shear stress (WSS) is also known as a contributing factor of the formation of atherosclerotic plaques. Since the causes of atherosclerosis cannot be attributed to a single factor, clearly understanding the mechanisms and causes of its occurrence is crucial for preventing the disease and developing effective treatment strategies. To better understand atherosclerosis and define the correlation between various contributing factors, computational fluid dynamics (CFD) analysis is primarily used. CFD simulates WSS, the frictional force caused by blood flow on the vessel wall with various hemodynamic changes. Using apolipoprotein E knockout (ApoE-KO) mice subjected to partial ligation and a high-fat diet at 1-week, 2-week, and 4-week intervals as an atherosclerosis model, CFD analysis was conducted along with the reconstruction of carotid artery blood flow via magnetic resonance imaging (MRI) and compared to the inflammatory factors and pathological staining. In this experiment, a comparative analysis of the effects of high WSS and low WSS was conducted by comparing the standard deviation of time-averaged wall shear stress (TAWSS) at each point within the vessel wall. As a novel approach, the standard deviation of TAWSS within the vessel was analyzed with the staining results and pathological features. Since the onset of atherosclerosis cannot be explained by a single factor, the aim was to find the correlation between the thickness of atherosclerotic plaques and inflammatory factors through standard deviation analysis. As a result, the gap between low WSS and high WSS widened as the interval between weeks in the atherosclerosis mouse model increased. This finding not only linked the occurrence of atherosclerosis to WSS differences but also provided a connection to the causes of vulnerable plaques.

Metagenomic analysis of atheroma plaques for identification of microorganisms indicates presence of Toxoplasma gondii as a possible etiological agent

BackgroundCardiovascular diseases (CVDs) are the leading cause of death worldwide. Vital organs like the heart are affected by the occlusion of blood vessels due to atherosclerotic plaque formation. However, the role of infectious agents has always been an essential subject of investigation. This study investigated the presence of microorganisms, including nanobacteria, in atherosclerotic plaques removed from human carotid arteries by microbiological and metagenomic examination. MethodsAtheroma plaque samples were obtained from 20 patients with carotid artery stenosis who had atherectomy by surgery or percutaneous intervention. Nanobacteria were grown by culturing homogenates of the atheroma plaques. Whole genome sequencing was done for samples. Because of the high percentage of Toxoplasma gondii (T. gondii) DNA, PCR investigation was applied to detect T. gondii DNA in the samples. ResultsA molecular analysis of nanobacteria revealed them to be made of human proteins, supporting the theory that they are not living organisms. According to sequencing results, samples showed that more than 50 % of the metagenomic sequences belonged to Toxoplasma gondii. PCR investigation indicated that T. gondii DNA was positive in 8 (40 %) of 20 plaques. ConclusionsFurther evidence regarding the role of T. gondii in the etiology of plaque formation may help determine the strategy for prevention and treatment of infections in preventing atheroma plaque formation in the future.

Involvement of interferon-gamma and tumor necrosis factor-alpha in the formation of unstable atherosclerotic plaque

Research on the role of various interleukins in atherosclerosis has shown that pro-inflammatory cytokines contribute to disease progression and destabilization of atherosclerotic plaques. The review presents the latest data from the scientific literature and the study’s own findings on the effects of pro-inflammatory cytokines INF-γ and TNF-α on the formation of unstable atherosclerotic lesions. It has been shown that the deterioration of the unstable plaque cap strength and its destruction can be associated with an increase in concentration, activation and action of powerful pro-inflammatory cytokines INF-γ and TNF-α in the vascular wall.