Atherosclerosis Formation Research Articles

Mechanisms and treatment of atherosclerosis: focus on macrophages

Macrophages are the basic mediators and coordinators of various types of chronic inflammation and play a crucial role in the formation and development of atherosclerosis (AS). In the complex microenvironment of atherosclerotic plaques, macrophages of different sources are exposed to different signal stimuli and thus polarized into various subpopulations. Various types of macrophages with predominantly M1 and M2 phenotypes also play different regulatory roles in the initiation and progression of AS. Lipid-lowering drugs, mainly statins, are widely used in clinical practice, but the adverse reactions are obvious and there is a lack of personalized treatment. Emerging targeted macrophage and Traditional Chinese medicine (TCM)-related therapies can regulate the cellular microenvironment, inhibit the polarization of M1 macrophages, and promote the activation of M2 macrophages, providing new ideas for the prevention and treatment of AS.

Chitosan oligosaccharides: A potential therapeutic agent for inhibiting foam cell formation in atherosclerosis

Foam cell formation is a key hallmark in atherosclerosis and associated cardiovascular diseases (CVDs). The potential anti-atherosclerotic potential of chitosan oligosaccharides (COS) was investigated using oxLDL-treated RAW264.7 murine cells. COS treatment led to a significant inhibition of lipid accumulation, as demonstrated by Oil Red O staining, and reduced levels of total cholesterol, free cholesterol, cholesterol esters, and triglycerides in.oxLDL-treated RAW264.7 cells. COS blocked cholesterol influx through down-regulating class A1 scavenger receptors (SR-A1) and cluster of differentiation 36 (CD36) expression and stimulated cholesterol efflux through up-regulating ABC transporters ABCA-1 and ABCG-1 expressions. Additionally, COS treatment stimulated nuclear signaling pathways involving peroxisome proliferator-activated receptor-γ (PPAR-γ) and liver X receptor α (LXR-α), and also led to the phosphorylation of AMP-activated protein kinase (AMPK). COS further demonstrated anti-inflammatory effects by inhibiting the production of pro-inflammatory cytokines and the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in oxLDL-treated RAW264.7 cells, through suppression of NF-κB signaling. Furthermore, COS alleviated oxidative stress induced by oxLDL by activating Nrf2 signaling and enhancing the expression of antioxidant genes, including heme oxygenase-1 (HO-1), superoxide dismutase (SOD), glutathione peroxidase (Gpx), and catalase (CAT). In conclusion, COS can be beneficial in preventing atherosclerosis and related diseases.

SPA Promotes Atherosclerosis Through Mediating Macrophage Foam Cell Formation-Brief Report.

Atherosclerosis is a progressive inflammatory disease in which macrophage foam cells play a central role in disease pathogenesis. SPA (surfactant protein A) is a lipid-associating protein involved with regulating macrophage function in various inflammatory diseases. However, the role of SPA in atherosclerosis and macrophage foam cell formation has not been investigated. SPA expression was assessed in healthy and atherosclerotic human coronary arteries and the brachiocephalic arteries of wild-type or ApoE-deficient mice fed high-fat diets for 4 weeks. Hypercholesteremic wild-type and SPA-deficient mice fed a high-fat diet for 6 weeks were investigated for atherosclerotic lesions in vivo. In vitro experiments using RAW264.7 macrophages, primary resident peritoneal macrophages extracted from wild-type or SPA-deficient mice, and human monocyte-derived macrophages from the peripheral blood of healthy donors determined the functional effects of SPA in macrophage foam cell formation. SPA expression was increased in atherosclerotic lesions in humans and ApoE-deficient mice and in response to a proatherosclerotic stimulus in vitro. SPA deficiency reduced the lipid profiles induced by hypercholesterolemia, attenuated atherosclerosis, and reduced the number of lesion-associated macrophage foam cells. In vitro studies revealed that SPA deficiency reduced intracellular cholesterol accumulation and macrophage foam cell formation. Mechanistically, SPA deficiency dramatically downregulated the expression of scavenger receptor CD36 (cluster of differentiation antigen 36) cellular and lesional expression. Importantly, SPA also increased CD36 expression in human monocyte-derived macrophages. Our results elucidate that SPA is a novel factor promoting atherosclerosis development. SPA enhances macrophage foam cell formation and atherosclerosis by increasing scavenger receptor CD36 expression, leading to increasing cellular OxLDL influx.

The novel anthraquinone compound Kanglexin prevents endothelial-to-mesenchymal transition in atherosclerosis by activating FGFR1 and suppressing integrin β1/TGFβ signaling.

Endothelial-mesenchymal transition (EndMT) disrupts vascular endothelial integrity and induces atherosclerosis. Active integrin β1 plays a pivotal role in promoting EndMT by facilitating TGFβ/Smad signaling in endothelial cells. Here, we report a novel anthraquinone compound, Kanglexin (KLX), which prevented EndMT and atherosclerosis by activating MAP4K4 and suppressing integrin β1/TGFβ signaling. First, KLX effectively counteracted the EndMT phenotype and mitigated the dysregulation of endothelial and mesenchymal markers induced by TGFβ1. Second, KLX suppressed TGFβ/Smad signaling by inactivating integrin β1 and inhibiting the polymerization of TGFβR1/2. The underlying mechanism involved the activation of FGFR1 by KLX, resulting in the phosphorylation of MAP4K4 and Moesin, which led to integrin β1 inactivation by displacing Talin from its β-tail. Oral administration of KLX effectively stimulated endothelial FGFR1 and inhibited integrin β1, thereby preventing vascular EndMT and attenuating plaque formation and progression in the aorta of atherosclerotic Apoe-/- mice. Notably, KLX (20 mg/kg) exhibited superior efficacy compared with atorvastatin, a clinically approved lipid-regulating drug. In conclusion, KLX exhibited potential in ameliorating EndMT and retarding the formation and progression of atherosclerosis through direct activation of FGFR1. Therefore, KLX is a promising candidate for the treatment of atherosclerosis to mitigate vascular endothelial injury.

Combination of Green Tea, Green Coffee, and Turmeric Extract Improve the THOC5 and AIF1, but not ACTA2 and CNN1 Gene Expression in the Aortic Tissue of Metabolic Syndrome Model

Metabolic syndrome (MetS) is a group of risk factors in the form of central obesity, insulin resistance, dyslipidemia, and hypertension, increasing oxidative stress. This pathological event leads to the development of cardiovascular disease, for instance, atherosclerosis. Besides modifiable risk factors, non-modifiable risk factors such as genetic factors also play a role in the formation of atherosclerosis in MetS conditions such as THOC5, AIF1, CNN1, and ACTA2. Recently, natural compound derivatives, such as epigallocatechin-3-gallate (EGCG), chlorogenic acid (CGA), and turmeric, have shown beneficial effects in MetS improvement. This study aimed to investigate the effect of green tea, green coffee, and turmeric extract on the expression of THOC5, AIF1, CNN1, and ACTA2 genes that contributed to atherosclerotic vasculopathy development in the MetS rat model. Twenty-five MetS rat models were grouped into 4 groups (n = 5): Standard control (SC), MetS (MetS), a combination of green tea, green coffee, and turmeric extract with treatment doses: 300/100/150 mg/BW(C1) and 400/200/250 mg/BW(C2) group. The THOC5, AIF1, CNN1, and ACTA2 expression were measured at the end of treatment periods. This study found that administering green tea, green coffee, and turmeric extract can lower the expression of THOC5, AIF1, CNN1, and ACTA2. The correlation test showed that there is a strong correlation between THOC5 and AIF1 gene expression, with positive value. In summary, the combined effects of green tea, green coffee, and curcumin extract show significant promise as a potential anti-atherosclerosis treatment by improve the THOC5 and AIF1, but not ACTA2 and CNN1 gene expression in the aortic tissue of metabolic syndrome model. HIGHLIGHTS Metabolic syndrome is a group of risk factors consist of central obesity, insulin resistance, dyslipidemia, and hypertension. Individuals with MetS have an increased risk of developing atherosclerotic cardiovascular disease. Besides modifiable risk factors, non-modifiable risk factors such as genetic factors also play a role in the formation of atherosclerosis in MetS conditions such as THOC5, AIF1, CNN1, and ACTA2. This study aimed to investigate the effect of green tea, green coffee, and turmeric extract on the expression of THOC5, AIF1, CNN1, and ACTA2 genes that contributed to atherosclerotic vasculopathy development in the MetS rat model. Administering green tea, green coffee, and turmeric extract can lower the expression of THOC5, AIF1, CNN1, and ACTA2. The correlation test showed that there is a strong correlation between THOC5 and AIF1 gene expression, with positive value. In summary, the combined effects of green tea, green coffee, and curcumin extract show significant promise as a potential anti-atherosclerosis treatment by improve the THOC5 and AIF1, but not ACTA2 and CNN1 gene expression in the aortic tissue of metabolic syndrome model. GRAPHICAL ABSTRACT

Oxidative stress disrupts vascular microenvironmental homeostasis affecting the development of atherosclerosis.

Atherosclerosis is primarily an inflammatory reaction of the cardiovascular system caused by endothelial damage, leading to progressive thickening and hardening of the vessel walls, as well as extensive necrosis and fibrosis of the surrounding tissues, the most necessary pathological process causing cardiovascular disease. When the body responds to harmful internal and external stimuli, excess oxygen free radicals are produced causing oxidative stress to occur in cells and tissues. Simultaneously, the activation of inflammatory immunological processes is followed by an elevation in oxygen free radicals, which directly initiates the release of cytokines and chemokines, resulting in a detrimental cycle of vascular homeostasis abnormalities. Oxidative stress contributes to the harm inflicted upon vascular endothelial cells and the decrease in nitric oxide levels. Nitric oxide is crucial for maintaining vascular homeostasis and is implicated in the development of atherosclerosis. This study examines the influence of oxidative stress on the formation of atherosclerosis, which is facilitated by the vascular milieu. It also provides an overview of the pertinent targets and pharmaceutical approaches for treating this condition.

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.

Huxin Formula Inhibits Oxidized low-Density Lipoprotein-Induced Foam Cell Formation in THP-1 Macrophages via the LOX-1/NF-κB Pathway

Background Macrophage-derived foam cells are essential in the progression of atherosclerosis (AS). Based on our previous study, the Huxin Formula (HXF), a traditional Chinese medicine formula, demonstrates potential in anti-atherosclerosis. Nevertheless, it is still unknown how HXF affects the formation of foam cells derived from THP-1 macrophages. Purpose This research aims to examine the preventive role of HXF in the development of foam cells and its underlying molecular mechanism. Methods THP-1 derived macrophages and THP-1 cells overexpressing LOX-1 (LV-OLR1) were exposed to ox-LDL to establish foam cell models, and then treated with HXF. Meantime, Oil red O staining was used to detect lipid droplet production. ELISA kit was performed to measure intracellular levels of IL-6 and TGF-β. RT-qPCR and Western Blot were then utilized to determine the LOX-1 and NF-κB mRNA/protein levels. Results The findings indicated that HXF treatment potently reduced the lipid accumulation, downregulated IL-6 levels and upregulated TGF-β levels. However, this impact was almost reversed when LOX-1 was overexpressed in THP-1 cells stimulated with ox-LDL. Moreover, THP-1 were treated with HXF markedly reduced the levels of LOX-1 and NF-κB mRNA/protein, whereas overexpressing LOX-1 significantly reversed this effect. Conclusion HXF reduced the formation of foam cell in ox-LDL-stimulated THP-1 macrophages via inhibiting lipid accumulation and inflammation through regulating the LOX-1/ NF-κB pathway. These present findings further indicate a potential beneficial role of HXF in ameliorating atherosclerosis and foam cell formation, while provide a novel potential therapeutic strategy for preventing atherosclerosis.

Smooth muscle-specific deletion of Ccn2 causes severe aorta malformation and atherosclerosis.

Cellular Communication Network Factor 2 (CCN2) is a matricellular protein implicated in fibrotic diseases, with ongoing clinical trials evaluating anti-CCN2-based therapies. By uncovering CCN2 as abundantly expressed in non-diseased artery tissue, this study aimed to investigate the hypothesis that CCN2 plays a pivotal role in maintaining smooth muscle cell (SMC) phenotype and protection against atherosclerosis. Global- and SMC-specific Ccn2 knockout mouse models were employed to demonstrate that Ccn2 deficiency leads to SMC de-differentiation, medial thickening, and aorta elongation under normolipidemic conditions. Inducing hyperlipidemia in both models resulted in severe aorta malformation and a 17-fold increase in atherosclerosis formation. Lipid-rich lesions developed at sites of the vasculature typically protected from atherosclerosis-development by laminar blood flow, covering 90% of aortas, and extending to other vessels, including coronary arteries. Evaluation at earlier time points revealed medial lipid accumulation as a lesion-initiating event. Fluorescently labelled LDL injection followed by confocal microscopy showed increased LDL retention in the medial layer of Ccn2 knockout aortas, likely attributed to marked proteoglycan enrichment of the medial extracellular matrix. Analyses leveraging data from the Athero-Express study cohort indicated relevance of CCN2 in established human lesions, as CCN2 correlated with SMC marker transcripts across 654 transcriptomically profiled carotid plaques. These findings were substantiated through in situ hybridization showing CCN2 expression predominantly in the fibrous cap. This study identifies CCN2 as a major constituent of the normal artery wall, critical in regulating SMC differentiation and aorta integrity, and possessing a protective role against atherosclerosis development. These findings underscore the need for further investigation into the potential effects of anti-CCN2-based therapies on the vasculature.

Catalpol inhibits HHcy-induced EndMT in endothelial cells by modulating ROS/NF-κB signaling

BackgroundHyperhomocysteinemia (HHcy) is an independent risk factor for atherosclerosis (AS). Endothelial mesenchymal transition (EndMT) refers to the process in which endothelial cells lose endothelial cell morphology and characteristic gene expression, and acquire phenotypic characteristics and gene expression related to mesenchymal cells. Numerous studies have confirmed that EndMT is involved in the formation of atherosclerosis. Catalpol is one of the active components of Rehmannia, which has antioxidant, anti-inflammatory, anti-tumor, neuroprotective and other biological activities. Studies have shown that catalpol can reduce atherosclerotic plaque induced by high sugar or fat. However, the effect of catalpol on HHCY-induced EndMT is unclear.Methods and resultsIn vitro HHcy-treated primary human umbilical vein endothelial cells (HUVECs) were used to construct a cell model, and the antioxidants N-acetylcysteine (NAC) and catalase alcohol were administered. In vivo C57BL/6N mice were given a diet fed with 4.4% high methionine chow to construct a HHcy mice model and were treated with catalpol. The results showed that hhcy could induce morphological transformation of endothelial cells into mesenchymal cells, increase intracellular ROS content, up-regulate α-SMA, N-cadherin, p-p65 protein expression, down-regulate VE-cadherin, CD31 protein expression, induce pathological changes of aortic root endothelium, and increase aortic endothelial ROS content. Catalpol reversed these hhcy induced outcomes.ConclusionsCatalpol inhibits HHcy-induced EndMT, and the underlying mechanism may be related to the ROS/NF-κB signaling pathway. Catalpol may be a potential drug for the treatment of HHcy-related AS.

FSGe: A fast and strongly-coupled 3D fluid–solid-growth interaction method

Equilibrated fluid–solid-growth (FSGe) is a fast, open source, three-dimensional (3D) computational platform for simulating interactions between instantaneous hemodynamics and long-term vessel wall adaptation through mechanobiologically equilibrated growth and remodeling (G&R). Such models can capture evolving geometry, composition, and material properties in health and disease and following clinical interventions. In traditional G&R models, this feedback is modeled through highly simplified fluid solutions, neglecting local variations in blood pressure and wall shear stress (WSS). FSGe overcomes these inherent limitations by strongly coupling the 3D Navier–Stokes equations for blood flow with a 3D equilibrated constrained mixture model (CMMe) for vascular tissue G&R. CMMe allows one to predict long-term evolved mechanobiological equilibria from an original homeostatic state at a computational cost equivalent to that of a standard hyperelastic material model. In illustrative computational examples, we focus on the development of a stable aortic aneurysm in a mouse model to highlight key differences in growth patterns between FSGe and solid-only G&R models. We show that FSGe is especially important in blood vessels with asymmetric stimuli. Simulation results reveal greater local variation in fluid-derived WSS than in intramural stress (IMS). Thus, differences between FSGe and G&R models became more pronounced with the growing influence of WSS relative to pressure. Future applications in highly localized disease processes, such as for lesion formation in atherosclerosis, can now include spatial and temporal variations of WSS.

Abstract Tu017: MerTK inhibition aggravates partial carotid ligation-induced atherosclerosis

Introduction: Partial carotid ligation (PCL) is a widely used model to generate acute disturbed flow (d-flow) in left carotid artery (LCA), leading to rapid endothelial dysfunction and atherosclerosis formation. While the right carotid artery (RCA) without PCL is a built-in control characterized by steady flow (s-flow). Endothelial cells (ECs) form a single cell layer that is constantly exposed to blood flow patterns and play important roles in atherosclerosis. MER proto-oncogene tyrosine kinase (MerTK) is the major receptor for efferocytosis, a process of the efficient clearance of apoptotic cells. MerTK is mainly expressed in macrophages and there are very limited reports focusing on MerTK function in ECs. This study was designed to investigate the role of blood flow patterns in regulating MerTK expression in aortic ECs and its contributions to the development of atherosclerosis. Methods: Partial carotid artery ligation combined with AAV-PCSK9 and high fat diet (HFD) were used to set up acute atherosclerosis within 4 weeks with WT and MerTK -/- mice. Proteomics and molecular experiments were applied to reveal the potential mechanism pathways. Results: Our proteomics data showed that, compared with WT group, MerTK -/- aggravates atherosclerosis in LCA through upregulation of endothelial dysfunction markers (e.g. IL-1β, NF-κB, TLR4, MAPK signaling) and mitochondrial dysfunction. Our immunostaining data further validates the proteomics data, showing that MerTK -/- induces impaired endothelial efferocytosis and expression of endothelial dysfunction markers (e.g., Caspase-3, NF-κB, TLR4, vWF, VCAM-1, and P22 phox ) and promotes the development of atherosclerosis. Conclusion: Our data suggests that endothelial MerTK is sensitive to d-flow and determines endothelial efferocytosis in vivo. MerTK inhibition promotes endothelial dysfunction and atherosclerosis. Our data may provide novel evidence and reference opinions for the application of endothelial MerTK- targeted therapeutics to treat atherosclerosis.

Loss of Smooth Muscle Tenascin-X Inhibits Vascular Remodeling Through Increased TGF-β Signaling.

Vascular smooth muscle cells (VSMCs) are highly plastic. Vessel injury induces a phenotypic transformation from differentiated to dedifferentiated VSMCs, which involves reduced expression of contractile proteins and increased production of extracellular matrix and inflammatory cytokines. This transition plays an important role in several cardiovascular diseases such as atherosclerosis, hypertension, and aortic aneurysm. TGF-β (transforming growth factor-β) is critical for VSMC differentiation and to counterbalance the effect of dedifferentiating factors. However, the mechanisms controlling TGF-β activity and VSMC phenotypic regulation under in vivo conditions are poorly understood. The extracellular matrix protein TN-X (tenascin-X) has recently been shown to bind TGF-β and to prevent it from activating its receptor. We studied the role of TN-X in VSMCs in various murine disease models using tamoxifen-inducible SMC-specific knockout and adeno-associated virus-mediated knockdown. In hypertensive and high-fat diet-fed mice, after carotid artery ligation as well as in human aneurysmal aortae, expression of Tnxb, the gene encoding TN-X, was increased in VSMCs. Mice with smooth muscle cell-specific loss of TN-X (SMC-Tnxb-KO) showed increased TGF-β signaling in VSMCs, as well as upregulated expression of VSMC differentiation marker genes during vascular remodeling compared with controls. SMC-specific TN-X deficiency decreased neointima formation after carotid artery ligation and reduced vessel wall thickening during Ang II (angiotensin II)-induced hypertension. SMC-Tnxb-KO mice lacking ApoE showed reduced atherosclerosis and Ang II-induced aneurysm formation under high-fat diet. Adeno-associated virus-mediated SMC-specific expression of short hairpin RNA against Tnxb showed similar beneficial effects. Treatment with an anti-TGF-β antibody or additional SMC-specific loss of the TGF-β receptor reverted the effects of SMC-specific TN-X deficiency. In summary, TN-X critically regulates VSMC plasticity during vascular injury by inhibiting TGF-β signaling. Our data indicate that inhibition of vascular smooth muscle TN-X may represent a strategy to prevent and treat pathological vascular remodeling.

The hemodynamic and geometric characteristics of carotid artery atherosclerotic plaque formation.

Ischemic stroke, which has a high incidence, disability, and mortality rate, is mainly caused by carotid atherosclerotic plaque. The difference in the geometric structures of the carotid arteries inevitably leads to the variability in the local hemodynamics, which plays a key role in the formation of carotid atherosclerosis. At present, the combined mechanisms of hemodynamic and geometric in the formation of carotid atherosclerotic plaque are not clear. Thus, this study characterized the geometric and hemodynamic characteristics of carotid atherosclerotic plaque formation using four-dimensional (4D) flow magnetic resonance imaging (MRI). Ultimately, 122 carotid arteries from 61 patients were examined in this study. According to the presence of plaques at the bifurcation of the carotid artery on cervical vascular ultrasound (US), carotid arteries were placed into a plaque group (N=69) and nonplaque group (N=53). The ratio of the maximum internal carotid artery (ICA) inner diameter to the maximum common carotid artery (CCA) inner diameter (ICA-CCA diameter ratio), bifurcation angle, and tortuosity were measured using neck three-dimensional time-of-flight magnetic resonance angiography (3D TOF-MRA). Meanwhile, 4D flow MRI was used to obtain the following hemodynamic parameters of the carotid arteries: volume flow rate, velocity, wall shear stress (WSS), and pressure gradient (PG). Independent sample t-tests were used to compare carotid artery geometry and hemodynamic changes between the plaque group and nonplaque group. The ICA-CCA diameter ratio between the plaque group and the nonplaque group was not significantly different (P=0.124), while there were significant differences in the bifurcation angle (P=0.005) and tortuosity (P=0.032). The bifurcation angle of the plaque group was greater than that of the nonplaque group (60.70°±20.75° vs. 49.32°±22.90°), and the tortuosity was smaller than that of the nonplaque group (1.07±0.04 vs. 1.09±0.05). There were no significant differences between the two groups in terms of volume flow rate (P=0.351) and the maximum value of velocity (velocitymax) (P=0.388), but the axial, circumferential, and 3D WSS values were all significantly different, including their mean values (all P values <0.001) and the maximum value of 3D WSS (P<0.001), with the mean axial, circumferential, 3D WSS values, along with the maximum 3D WSS value, being lower in the plaque group. The two groups also differed significantly in terms of maximum PG value (P=0.030) and mean PG value (P=0.026), with these values being greater in the nonplaque group than in the plaque group. A large bifurcation angle and a low tortuosity of the carotid artery are geometric risk factors for plaque formation in this area. Low WSS and low PG values are associated with carotid atherosclerotic plaque formation.

Correlation of Hba1c, Triglyceride, HDL with the Degree of Stenosis in Coronary Heart Patients with Type 2 Diabetes Mellitus

Background: Coronary Heart Disease (CHD) is a disease caused by the narrowing of the coronary artery wall as a result of the atherosclerosis process. Atherosclerosis plays an important role from the beginning of plaque formation until plaque rupture which causes blood clots. Diabetes mellitus and dyslipidemia are one of the major risk factors for CHD. In patients with type 2 Diabetes Mellitus, there was an altered lipid profile which led to endothelial damage that caused the formation of atherosclerosis. HDL cholesterol labeled as good cholesterol was decreased due to uncontrolled LDL cholesterol labeled as bad cholesterol. LDL cholesterol synthesis process was disrupted then causing plaque formation in the arteries which causes CHD. Aim: The aim of this study was to analysis correlation between HbA1c levels, triglyceride levels, HDL levels and the degree of stenosis in coronary heart disease sufferers with type 2 diabetes mellitus. Method: This study was an observational cross-sectional analytical study with total of 51 patients with CHD who underwent cardiac catheterization at Telogorejo Hospital. Semarang. The correlation test in this study using the Spearman test with p 0.05 is considered significant. Results: Results of this study show that there is no significant correlation between HbA1C levels and triglyceride levels (p= 0.793), and Hba1C with the degree of stenosis was (p= 0.685) but, there was significant correlation between HDL cholesterol level with the degree of stenosis (p=0.015). Conclusion: It was concluded that there was no significant correlation between the correlation of HbA1c levels and triglyceride levels with the degree of stenosis and there was a moderately negative significant correlation between HDL levels and the degree of stenosis.

The ABCA1 gene polymorphisms rs1800977 and rs2230806 are differentially associated with the risk for myocardial infarction in Slovenian subjects with type 2 diabetes mellitus

BackgroundThe adenosine triphosphate-binding cassette transporter A1 (ABCA1) is closely linked to various aspects of the regulation of whole-body cholesterol metabolism and atherosclerosis formation. The object of the study was to investigate the association between rs1800977 and rs2230806 polymorphisms in the ABCA1 gene and myocardial infarction (MI) in Slovenian subjects with type 2 diabetes mellitus (T2DM). Methods1590 T2DM patients (484 subjects with MI and 1106 controls) were included in this retrospective cross-sectional case–control study. After genotyping, Pearson χ2 test was used to compare the distribution of genotypes and alleles among the two groups. Logistic regression analysis adjusted for several risk factors for MI was performed. ResultsGenotype distribution showed significant association with MI in T2DM subjects for both selected polymorphisms in ABCA1 gene (p = 0.009 for rs2230806 and p = 0.042 for rs1800977). After applying corrections for confounding variables like age, waist circumference, diastolic blood pressure, serum high-density lipoprotein levels, gender and smoking several genetic models still showed significant associations with MI (dominant model for rs2230806 and dominant, overdominant and co-dominant for rs1800977). ConclusionOur study showed that presence of the T allele of the rs2230806 ABCA1 gene is associated with higher risk of MI, while the A allele of the rs1800977 conferred protection against MI in Slovenian T2DM subjects.

Early diagnostic value of carotid artery ultrasound parameters combined with epicardial adipose layer thickness in coronary heart disease

BACKGROUND Coronary heart disease is associated with coronary atherosclerosis indicated by carotid intima-media thickness (CIMT) thickening and altered vascular elasticity. The epicardial adipose layer can secrete proinflammatory factors that promote the formation of coronary atherosclerosis. Thus, the epicardial fat layer thickness (EAT) may also predict coronary heart disease. AIM To determine the role of common carotid artery ultrasound parameters and EAT in the early diagnosis of coronary artery disease. METHODS Based on coronary angiography, patients with newly suspected coronary heart disease were divided into case (n = 107) and control (n = 41) groups. The carotid ultrasound parameters, including vascular stiffness (β), elastic coefficient (EP), pulse wave conduction velocity (PWV-β), CIMT, and EAT were compared between the case and control groups and among patients with different lesion numbers in the case group. Pearson correlation was used to evaluate the early diagnostic value of EAT, common carotid artery elasticity, and CIMT for coronary heart disease. RESULTS EP, β, PWV-β, CIMT, and EAT were significantly higher in the case group compared with the levels in the control group (all P &lt; 0.001). In the case group, lesions were detected in one vessel in 34 patients, two vessels in 38 patients, and three vessels in 35 patients. Within the case group, β, EP, PWV-β, CIMT, and EAT levels significantly increased with an increased number of lesions (all P &lt; 0.001). EAT positively correlated with β, EP, PWV-β, and CIMT (all P &lt; 0.01). The area under the curve for diagnosing coronary heart disease using EAT combined with CIMT and carotid elasticity was 0.893, and the sensitivity and specificity were 0.890 and 0.837. CONCLUSION EAT correlated well with changes in carotid artery elasticity and CIMT in patients with coronary heart disease. The combination of EAT, carotid artery elasticity, and CIMT facilitates the early diagnosis of coronary heart disease.

Guizhitongluo Tablet inhibits atherosclerosis and foam cell formation through regulating Piezo1/NLRP3 mediated macrophage pyroptosis

BackgroundAtherosclerosis (AS) is the main pathological basis for the development of cardiovascular diseases. Vascular inflammation is an important factor in the formation of AS, and macrophage pyroptosis plays a key role in AS due to its unique inflammatory response. Guizhitongluo Tablet (GZTLT) has shown clinically effective in treating patients with AS, but its mechanism is elusive. PurposeThis study was to determine the effects of GZTLT on atherosclerotic vascular inflammation and pyroptosis and to understand its underlying mechanism. Materials and methodsThe active constituents of GZTLT were analysed by means of UPLC-HRMS. In vivo experiments were performed using ApoE−/− mice fed a high fat diet for 8 weeks, followed by treatment with varying concentrations of GZTLT orally by gavage and GsMTx4 (GS) intraperitoneally and followed for another 8 weeks. Oil red O, Haematoxylin-eosin (HE) and Masson staining were employed to examine the lipid content, plaque size, and collagen fibre content of the mouse aorta. Immunofluorescence staining was utilised to identify macrophage infiltration, as well as the expression of Piezo1 and NLRP3 proteins in aortic plaques. The levels of aortic inflammatory factors were determined using RT-PCR and ELISA. In vitro, foam cell formation in bone marrow-derived macrophages (BMDMs) was observed using Oil Red O staining. Intracellular Ca2+ measurements were performed to detect the calcium influx in BMDMs, and the expression of NLRP3 and its related proteins were detected by Western blot. ResultsThe UPLC-HRMS analysis revealed 31 major components of GZTLT. Our data showed that GZTLT inhibited aortic plaque formation in mice and increased plaque collagen fibre content to stabilise plaques. In addition, GZTLT could restrain the expression of serum lipid levels and suppress macrophage foam cell formation. Further studies found that GZTLT inhibited macrophage infiltration in aortic plaques and suppressed the expression of inflammatory factors. It is noteworthy that GZTLT can restrain Piezo1 expression and reduce Ca2+ influx in BMDMs. Additionally, we found that GZTLT could regulate NLRP3 activation and pyroptosis by inhibiting Piezo1. ConclusionThe present study suggests that GZTLT inhibits vascular inflammation and macrophage pyroptosis through the Piezo1/NLRP3 signaling pathway, thereby delaying AS development. Our finding provides a potential target for AS treatment and drug discovery.

Radiomics of pericoronary adipose tissue on computed tomography angiography predicts coronary heart disease in patients with type 2 diabetes mellitus

BackgroundDiabetes is a common chronic metabolic disease. The progression of the disease promotes vascular inflammation and the formation of atherosclerosis, leading to cardiovascular disease. The coronary artery perivascular adipose tissue attenuation index based on CCTA is a new noninvasive imaging biomarker that reflects the spatial changes in perivascular adipose tissue attenuation in CCTA images and the inflammation around the coronary arteries. In this study, a radiomics approach is proposed to extract a large number of image features from CCTA in a high-throughput manner and combined with clinical diagnostic data to explore the predictive ability of vascular perivascular adipose imaging data based on CCTA for coronary heart disease in diabetic patients.MethodsR language was used for statistical analysis to screen the variables with significant differences. A presegmentation model was used for CCTA vessel segmentation, and the pericoronary adipose region was screened out. PyRadiomics was used to calculate the radiomics features of pericoronary adipose tissue, and SVM, DT and RF were used to model and analyze the clinical data and radiomics data. Model performance was evaluated using indicators such as PPV, FPR, AAC, and ROC.ResultsThe results indicate that there are significant differences in age, blood pressure, and some biochemical indicators between diabetes patients with and without coronary heart disease. Among 1037 calculated radiomic parameters, 18.3% showed significant differences in imaging omics features. Three modeling methods were used to analyze different combinations of clinical information, internal vascular radiomics information and pericoronary vascular fat radiomics information. The results showed that the dataset of full data had the highest ACC values under different machine learning models. The support vector machine method showed the best specificity, sensitivity, and accuracy for this dataset.ConclusionsIn this study, the clinical data and pericoronary radiomics data of CCTA were fused to predict the occurrence of coronary heart disease in diabetic patients. This provides information for the early detection of coronary heart disease in patients with diabetes and allows for timely intervention and treatment.

Anti-Inflammatory Responses Produced with Nippostrongylus brasiliensis-Derived Uridine via the Mitochondrial ATP-Sensitive Potassium Channel and Its Anti-Atherosclerosis Effect in an Apolipoprotein E Gene Knockout Mouse Model.

Atherosclerosis (AS) has become the leading cause of cardiovascular disease worldwide. Our previous study had observed that Nippostrongylus brasiliensis (Nb) infection or its derived products could inhibit AS development by inducing an anti-inflammatory response. We performed a metabolic analysis to screen Nb-derived metabolites with anti-inflammation activity and evaluated the AS-prevention effect. We observed that the metabolite uridine had higher expression levels in mice infected with the Nb and ES (excretory-secretory) products and could be selected as a key metabolite. ES and uridine interventions could reduce the pro-inflammatory responses and increase the anti-inflammatory responses in vitro and in vivo. The apolipoprotein E gene knockout (ApoE-/-) mice were fed with a high-fat diet for the AS modeling. Following the in vivo intervention, ES products or uridine significantly reduced serum and liver lipid levels, alleviated the formation of atherosclerosis, and reduced the pro-inflammatory responses in serum or plaques, while the anti-inflammatory responses showed opposite trends. After blocking with 5-HD (5-hydroxydecanoate sodium) in vitro, the mRNA levels of M2 markers were significantly reduced. When blocked with 5-HD in vivo, the degree of atherosclerosis was worsened, the pro-inflammatory responses were increased compared to the uridine group, while the anti-inflammatory responses decreased accordingly. Uridine, a key metabolite from Nippostrongylus brasiliensis, showed anti-inflammatory and anti-atherosclerotic effects in vitro and in vivo, which depend on the activation of the mitochondrial ATP-sensitive potassium channel.