Foam Cells Research Articles

The role of transcription factors in the pathogenesis and therapeutic targeting of vascular diseases.

Transcription factors (TFs) constitute an essential component of epigenetic regulation. They contribute to the progression of vascular diseases by regulating epigenetic gene expression in several vascular diseases. Recently, numerous regulatory mechanisms related to vascular pathology, ranging from general TFs that are continuously activated to histiocyte-specific TFs that are activated under specific circumstances, have been studied. TFs participate in the progression of vascular-related diseases by epigenetically regulating vascular endothelial cells (VECs) and vascular smooth muscle cells (VSMCs). The Krüppel-like family (KLF) TF family is widely recognized as the foremost regulator of vascular diseases. KLF11 prevents aneurysm progression by inhibiting the apoptosis of VSMCs and enhancing their contractile function. The presence of KLF4, another crucial member, suppresses the progression of atherosclerosis (AS) and pulmonary hypertension by attenuating the formation of VSMCs-derived foam cells, ameliorating endothelial dysfunction, and inducing vasodilatory effects. However, the mechanism underlying the regulation of the progression of vascular-related diseases by TFs has remained elusive. The present study categorized the TFs involved in vascular diseases and their regulatory mechanisms to shed light on the potential pathogenesis of vascular diseases, and provide novel insights into their diagnosis and treatment.

Naringin Inhibits Macrophage Foam Cell Formation by Regulating Lipid Homeostasis and Metabolic Phenotype.

Imbalances in lipid uptake and efflux and inflammation are major contributors to foam cell formation, which is considered a therapeutic target to protect against atherosclerosis. Naringin, a citrus flavonoid abundant in citrus fruits, has been reported to exert an antiatherogenic function, but its pharmacological mechanism is unclear. Naringin treatment effectively inhibits foam cell formation in THP-1 and RAW264.7 macrophages. In this study, mechanically, naringin maintained lipid homeostasis within macrophages through downregulation of the key genes for lipid uptake (MSR1 and CD36) and the upregulation of ABCA1, ABCG1 and SR-B1, which are responsible for cholesterol efflux. Meanwhile, naringin significantly decreased the cholesterol synthesis-related genes and increased the genes involved in cholesterol metabolism. Subsequently, the results showed that ox-LDL-induced macrophage inflammatory responses were inhibited by naringin by reducing the proinflammatory cytokines IL-1β, IL-6 and TNF-α, and increasing the anti- inflammatory cytokine IL-10, which was further verified by the downregulation of pro-inflammatory and chemokine-related genes. Additionally, we found that naringin reprogrammed the metabolic phenotypes of macrophages by suppressing glycolysis and promoting lipid oxidation metabolism to restore macrophage phenotypes and functions. These results suggest that naringin is a potential drug for the treatment of AS as it inhibits macrophage foam cell formation by regulating metabolic phenotypes and inflammation.

P2X7 receptor is essential for ST36-attenuated cardiac fibrosisupon beta-adrenergic insult.

P2X7 receptor (P2X7R) plays an important role in modulating inflammation and fibrosis, but information is limited whether Zusanli (ST36) can inhibit inflammation and fibrosis by regulating P2X7R. Isoprenaline at 5mg/kg was subcutaneously injected to wild-type and P2X7R knockout mice for 7 days, while treatment groups received electroacupuncture (EA) stimulation at ST36 for 7 sessions. Following 7-session treatment, Masson's trichrome staining was performed to assess the fibrosis. Morphology, electrocardiogram, and echocardiography were carried out to evaluate the cardiac function and structure. Western blotting, hematoxylin and eosin staining, immunohistochemistry, and biochemical analysis of inflammatory cytokine and transmission electron microscopy were carried out to characterize the effect of ST36 on inflammation. P2X7R was overexpressed in ISO-treated mice. EA at ST36, but not at non-points, reduced ISO-induced cardiac fibrosis, increases in HW/BW, R+S wave relative to mice in ISO groups. In addition, EA at ST36 downregulated ISO-upregulated P2X7R and NLRP3 in ventricle. Moreover, EA reduced cytokines of IL-1β, IL-6, and IL-18 in serum, and inhibited foam cell gathering, inflammatory cell infiltration, and autophagy. However, EA at ST36 failed to attenuate the cardiac fibrosis and hypertrophy in P2X7R knockout mice. In conclusion, EA at ST36 attenuated ISO-induced fibrosis possibly via P2X7R.

Transcriptomic analysis reveals the critical role of chemokine signaling in the anti-atherosclerosis effect of Xuefu Zhuyu decoction

Ethnopharmacological relevanceThe process of atherosclerosis (AS) is complicated. Transcriptomics technology can assist in discovering the underlying mechanisms and exploring the key targets of Traditional Chinese Medicine (TCM) against atherosclerosis. AimThis study aimed to investigate targets and signaling pathways significantly related to AS and the potential intervention targets of Xuefu Zhuyu decoction by transcriptomics. Materials and methodsAS models were established by subjecting ApoE-/-mice to an 8-week high-fat diet. Structural changes and plaque formation in the aortic root were observed using hematoxylin-eosin staining (HE staining), while Oil Red O staining was employed to visualize lipid deposition within the aortic root plaque. Movat staining and immunohistochemical staining were conducted to examine the components present in the aortic root plaque. Macrophage content within the plaque was observed through immunofluorescence. Additionally, mRNA sequencing was performed on aortic tissues to identify differentially expressed genes. Enrichment analysis was performed using GO and KEGG analysis. Visualization of the protein-protein interaction (PPI) network was achieved using Cytoscape 3.7.1 and STRING. Western blotting (WB) was employed to assess the protein expression of major differentially expressed genes in the aortic tissue. The drug freeze-dried powder of Xuefu Zhuyu decoction was prepared and the RAW264.7 cells were induced by lipopolysaccharide (LPS) to build an in vitro model. Real-time quantitative PCR was employed to measure the mRNA expression of major differential genes. ResultsAfter ApoE-/- mice were fed with an 8-week high-fat diet, observable changes included the thinning of the aortic root wall, the accumulation of foam cells within the plaque, and the formation of cholesterol crystals in the model group. Treatment with Xuefu Zhuyu (XFZY) decoction for 12 weeks significantly reduced the lipid deposition and the number of macrophages (P < 0.05) and significantly increased the collagen content within the plaque (P < 0.01). Enrichment analysis revealed a high enrichment of the Cytokine-cytokine receptor interaction pathway and Chemokine signaling pathway. Noteworthy genes involved in this response included Ccl12, Ccl22, Cx3cr1, Ccr7, Ccr2, Tnfrsf25, and Gdf5. Xuefu Zhuyu decoction significantly downregulated the expression of CX3CL1 and CX3CR1 (P < 0.05) and upregulated the expression of GDF5 (P < 0.01). Compared with control group, in cell models, the mRNA expressions of Ccl12, Ccl22, and Ccr2 were significantly upregulated (P < 0.05 or P < 0.01). Xuefu Zhuyu decoction significantly downregulated the expression of Ccl12, Ccl22, Cx3cr1, Ccr7 and Ccr2 (P < 0.05 or P < 0.01). ConclusionXuefu Zhuyu decoction demonstrates effective regulation of plaque components, retarding plaque progression and preserving plaque stability by modulating lipid metabolism and inflammatory responses. Subsequent transcriptome analysis identified the Cytokine-cytokine receptor interaction and Chemokine signaling pathway as potential key pathways for the therapeutic effects of Xuefu Zhuyu decoction. This insight not only provides crucial avenues for further exploration into the mechanisms underlying Xuefu Zhuyu decoction but also offers valuable perspectives and hypotheses for enhancing disease prevention and treatment strategies.

Multiparameter Assessment of Foam Cell Formation Progression Using a Dual-Color Switchable Fluorescence Probe.

The assessment of atherosclerosis (AS) progression has emerged as a prominent area of research. Monitoring various pathological features of foam cell (FC) formation is imperative to comprehensively assess AS progression. Herein, a simple benzospiropyran-julolidine-based probe, BSJD, with switchable dual-color imaging ability was developed. This probe can dynamically and reversibly adjust its molecular structure and fluorescent properties in different polar and pH environments. Such a polarity and pH dual-responsive characteristic makes it superior to single-responsive probes in dual-color imaging of lipid droplets (LDs) and lysosomes as well as monitoring their interaction. By simultaneously tracking various pathological features, including LD accumulation and size changes, lysosome dysfunction, and dynamically regulated lipophagy, more comprehensive information can be obtained for multiparameter assessment of FC formation progression. Using BSJD, not only the activation of lipophagy in the early stages and inhibition in the later phases during FC formation are clearly observed but also the important roles of lipophagy in regulating lipid metabolism and alleviating FC formation are demonstrated. Furthermore, BSJD is demonstrated to be capable of rapidly imaging FC plaque sites in AS mice with fast pharmacokinetics. Altogether, BSJD holds great promise as a dual-color organelle-imaging tool for investigating disease-related LD and lysosome changes and their interactions.

Uncovering the Role of Anmeidan against Atherosclerosis from Integrated Network Pharmacology and Pharmacological Experiments.

Atherosclerosis (AS) is the leading cause of mortality in elderly individuals worldwide. Anmeidan (AMD) is a Traditional Chinese Medicine (TCM) formula composed of many herbs, many of which have been accepted for treating AS. This study aimed to explore whether AMD can inhibit the progress of AS and its possible mechanism. ApoE-/- mice were used to establish the AS model and evaluate the therapeutic effect of AMD on AS. Based on network pharmacology technology, the potential mechanism of AMD for treating AS was explored, and lipid metabolism pathways related to AS were mainly studied. Next, the effects of AMD on liver lipid levels, antioxidant capacity, liver tissue morphology, and gene expression related to lipid metabolism in ApoE-/- mice were investigated. Cellular experiments were performed to confirm the lipid-lowering effect of AMD. Finally, the AMD composition was determined using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In ApoE-/- mice, AMD effectively alleviated AS by reducing serum total cholesterol, triglyceride, low-density lipoprotein levels, and plaque area, and increasing high-density lipoprotein levels. Network pharmacology indicated that AMD may suppress AS by regulating lipid metabolism pathways with multiple TCM components, which is consistent with the results of in vivo experiments and LC-MS/MS component identification. AMD significantly reduced liver lipid aggregation, intensified antioxidant enzyme activity, and upregulated the mRNA levels of ABCA1, ABCG1, and LDLR with increased cholesterol efflux. In addition, AMD decreased cholesterol levels in foam cells. This study confirmed that AMD could treat AS by regulating lipid metabolism and preliminarily explored the related mechanism. These findings provide new ideas for the treatment of AS with TCM.

Compressive Mechanical Behavior and Corresponding Failure Mechanism of Polymethacrylimide Foam Induced by Thermo-Mechanical Coupling.

Thermal-mechanical coupling during the molding process can cause compressive yield in the polymer foam core and then affect the molding quality of the sandwich structure. This work investigates the compressive mechanical properties and failure mechanism of polymethacrylimide (PMI) foam in the molding temperature range of 20-120 °C. First, the DMA result indicates that PMI foam has minimal mechanical loss in the 20~120 °C range and can be regarded as an elastoplastic material, and the TGA curve further proves that the PMI foam is thermally stable within 120 °C. Then, the compression results show that compared with 20 °C, the yield stress and elastic modulus of PMI foam decrease by 22.0% and 17.5% at 80 °C and 35.2% and 31.4% at 120 °C, respectively. Meanwhile, the failure mode changes from brittle fracture to plastic yield at about 80 °C. Moreover, a real representative volume element (rRVE) of PMI foam is established by using Micro-CT and Avizo 3D reconstruction methods, and the simulation results indicate that PMI foam mainly shows brittle fractures at 20 °C, while both brittle fractures and plastic yield occur at 80 °C, and most foam cells undergo plastic yield at 120 °C. Finally, the simulation based on a single-cell RVE reveals that the air pressure inside the foam has an obvious influence of about 6.7% on the yield stress of PMI foam at 80 °C (brittle-plastic transition zone).

Glucagon-like peptide-1 receptor agonists: new strategies and therapeutic targets to treat atherosclerotic cardiovascular disease.

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of cardiovascular mortality and is increasingly prevalent in our population. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) can safely and effectively lower glucose levels while concurrently managing the full spectrum of ASCVD risk factors and improving patients' long-term prognosis. Several cardiovascular outcome trials (CVOTs) have been carried out to further investigate the cardiovascular benefits of GLP-1RAs. Analyzing data from CVOTs can provide insights into the pathophysiologic mechanisms by which GLP-1RAs are linked to ASCVD and define the use of GLP-1RAs in clinical practice. Here, we discussed various mechanisms hypothesized in previous animal and preclinical human studies, including blockade of the production of adhesion molecules and inflammatory factors, induction of endothelial cells' synthesis of nitric oxide, protection of mitochondrial function and restriction of oxidative stress, suppression of NOD-like receptor thermal protein domain associated protein three inflammasome, reduction of foam cell formation and macrophage inflammation, and amelioration of vascular smooth muscle cell dysfunction, to help explain the cardiovascular benefits of GLP-1RAs in CVOTs. This paper provides an overview of the clinical research, molecular processes, and possible therapeutic applications of GLP-1RAs in ASCVD, while also addressing current limitations in the literature and suggesting future research directions.

Long Non-Coding RNA Nuclear-Enriched Abundant Transcript 1 (NEAT1) Facilitates Foam Cell Formation and Atherosclerosis Progression Through the miR-17-5p/Itchy E3 Ubiquitin Protein Ligase (ITCH)/Liver Kinase B1 (LKB1) Axis.

Foam cell formation is an important step for atherosclerosis (AS) progression. We investigated the mechanism by which the long non-coding RNA (lncRNA) nuclear-enriched abundant transcript 1 (NEAT1) regulates foam cell formation during AS progression.Methods and Results: An in vivo AS model was created by feeding ApoE-/-mice a high-fat diet. Oxidized low-density lipoprotein (ox-LDL)-stimulated macrophages were used as a cellular AS model. Interactions between NEAT1, miR-17-5p, itchy E3 ubiquitin protein ligase (ITCH) and liver kinase B1 (LKB1) were analyzed. NEAT1 and ITCH were highly expressed in clinical samples collected from 10 AS patients and in ox-LDL-treated macrophages, whereas expression of both miR-17-5p and LKB1 was low. ITCH knockdown inhibited ox-LDL-induced lipid accumulation and LDL uptake in macrophages. Mechanistically speakingly, ITCH promoted LDL uptake and lipid accumulation in macrophages by mediating LKB1 ubiquitination degradation. NEAT1 knockdown reduced LDL uptake and lipid accumulation in macrophages and AS progression in vivo. NEAT1 promoted ITCH expression in macrophages by acting as a sponge for miR-17-5p. Inhibition of miR-17-5p facilitated ox-LDL-induced increase in LDL uptake and lipid accumulation in macrophages, which was reversed by NEAT1/ITCH knockdown. NEAT1 accelerated foam cell formation during AS progression through the miR-17-5p/ITCH/LKB1 axis.

ASYMPTOTIC STABILITY FOR A FREE BOUNDARY MODEL OF AN ATHEROSCLEROTIC PLAQUE FORMATION IN THE PRESENCE OF REVERSE CHOLESTEROL TRANSPORT WITH HOLLING TYPE-III FUNCTIONAL RESPONSE

Atherosclerosis, as a chronic inflammatory disease, has been a threat to human health. How to diagnose and prevent this disease has long been the focus of medical and biomathematics study. In this paper, we investigate a free boundary model of an atherosclerotic plaque formation in the presence of reverse cholesterol transport, which includes low-density lipoprotein, high-density lipoprotein, endothelial stimulating cytokines, pro-inflammatory and anti-inflammatory macrophages, as well as foam cells. For this model, we use the Holling type-III response function instead of the usual Holling type-II to describe the change of the concentration of each substance. We first introduce the auxiliary function [Formula: see text] to prove the existence and uniqueness of small radially symmetric stationary plaque for appropriate [Formula: see text] and [Formula: see text] by using the contraction mapping principle and maximum principle, and then establish a condition to ensure their asymptotic stability behavior by expanding the corresponding steady-state solution.

Recombinant human proteoglycan 4 lowers inflammation and atherosclerosis susceptibility in female low-density lipoprotein receptor knockout mice.

Recombinant human proteoglycan 4 (rhPRG4) is a macromolecular mucin-like glycoprotein that is classically studied as a lubricant within eyes and joints. Given that endogenously produced PRG4 is present within atherosclerotic lesions and genetic PRG4 deficiency increases atherosclerosis susceptibility in mice, in the current study we investigated the anti-atherogenic potential of chronic rhPRG4 treatment. Female low-density lipoprotein receptor knockout mice were fed an atherogenic Western-type diet for 6 weeks and injected three times per week intraperitoneally with 0.5mg rhPRG4 or PBS as control. Treatment with rhPRG4 was associated with a small decrease in plasma-free cholesterol levels, without a change in cholesteryl ester levels. A marked increase in the number of peritoneal foam cells was detected in response to the peritoneal rhPRG4 administration, which could be attributed to elevated peritoneal leukocyte MSR1 expression levels. However, rhPRG4-treated mice exhibited significantly smaller aortic root lesions of 278 ± 21 × 103μm2 compared with 339 ± 15 × 103μm2 in the aortic root of control mice. The overall decreased atherosclerosis susceptibility coincided with a shift in the monocyte and macrophage polarization states towards the patrolling and anti-inflammatory M2-like phenotypes, respectively. Furthermore, rhPRG4 treatment significantly reduced macrophage gene expression levels as well as plasma protein levels of the pro-inflammatory/pro-atherogenic cytokine TNF-alpha. In conclusion, we have shown that peritoneal administration and subsequent systemic exposure to rhPRG4 beneficially impacts the inflammatory state and reduces atherosclerosis susceptibility in mice. Our findings highlight that PRG4 is not only a lubricant but also acts as an anti-inflammatory agent. KEY POINTS: Endogenously produced proteoglycan 4 is found in atherosclerotic lesions and its genetic deficiency in mice is associated with enhanced atherosclerosis susceptibility. In this study we investigated the anti-atherogenic potential of chronic treatment with recombinant human PRG4 in hypercholesterolaemic female low-density lipoprotein receptor knockout mice. We show that recombinant human PRG4 stimulates macrophage foam cell formation, but also dampens the pro-inflammatory state of monocyte/macrophages, eventually leading to a significant reduction in plasma TNF-alpha levels and a lowered atherosclerosis susceptibility. Our findings highlight that peritoneal recombinant human PRG4 treatment can execute effects both locally and systemically and suggest that it will be of interest to study whether rhPRG4 treatment is also able to inhibit the progression and/or induce regression of previously established atherosclerotic lesions.

C1q/Tumor Necrosis Factor-Related Protein-9 Enhances Macrophage Cholesterol Efflux and Improves Reverse Cholesterol Transport via AMPK Activation.

Cholesterol efflux from foam cells in atherosclerotic plaques is crucial for reverse cholesterol transport (RCT), an important antiatherogenic event. ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, are key receptors in the cholesterol efflux pathway. C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly discovered adipokine and exhibits an atheroprotective activity. However, the role of CTRP9 in RCT still remains unknown. In this work, we investigated the effect of subcutaneous administration of CTRP9 protein on RCT and atherosclerotic lesion formation in ApoE-/- mice fed with a high-fat diet. CTRP9-dependent regulation of cholesterol efflux and ABC transporters in RAW 264.7 foam cells was determined. Our results showed that CTRP9 protein decreased atherosclerotic lesions, increased cholesterol efflux, and upregulated liver ABCA1 and ABCG1 expression in ApoE-/- mice. CTRP9 treatment dose-dependently increased mRNA and protein expression of ABCA1, ABCG1, and LXR-α in RAW 264.7 foam cells. Moreover, the expression and phosphorylation of AMPK was potentiated upon CTRP9 treatment. Notably, CTRP9-induced cholesterol efflux and upregulation of ABCA, ABCG1, and LXR-α were impaired when AMPK was knocked down. AMPK depletion restored cholesterol accumulation in CTRP9-treated RAW 264.7 cells. Taken together, subcutaneous injection is an effective novel delivery route for CTRP9 protein, and exogenous CTRP9 can facilitate cholesterol efflux and promote RCT in an animal model of atherosclerosis. The atheroprotective activity of CTRP9 is mediated through the activation of AMPK signaling.

Geniposide ameliorates atherosclerosis by restoring lipophagy via suppressing PARP1/PI3K/AKT signaling pathway

BackgroundAtherosclerosis (AS) is the leading cause of global death, which manifests as arterial lipid stack and plaque formation. Geniposide is an iridoid glycoside extract from Gardenia jasminoides J.Ellis that ameliorates AS by mediating autophagy. However, how Geniposide regulates autophagy and treats AS remains unclear. PurposeTo evaluate the efficacy and mechanism of Geniposide in treating AS.Study design and methods: Geniposide was administered to high-fat diet-fed ApoE−/− mice and oxidized low-density lipoprotein-incubated primary vascular smooth muscle cells (VSMCs). AS was evaluated with arterial lipid stack, plaque progression, and collagen loss in the artery. Foam cell formation was detected by lipid accumulation, inflammation, apoptosis, and the expression of foam cell markers. The mechanism of Geniposide in treating AS was assessed using network pharmacology. Lipophagy was measured by lysosomal activity, expression of lipophagy markers, and the co-localization of lipids and lipophagy markers. The effects of lipophagy were blocked using Chloroquine. The role of PARP1 was assessed by Olaparib (a PARP1 inhibitor) intervention and PARP1 overexpression. ResultsIn vivo, Geniposide reversed high-fat diet-induced hyperlipidemia, plaque progression, and inflammation. In vitro, Geniposide inhibited VSMC-derived foam cell formation by suppressing lipid stack, apoptosis, and the expressions of foam cell markers. Network pharmacological analysis and in vitro validation suggested that Geniposide treated AS by enhancing lipophagy via suppressing the PI3K/AKT signaling pathway. The benefits of Geniposide in alleviating AS were offset by Chloroquine in vivo and in vitro. Inhibiting PARP1 using Olaparib promoted lipophagy and alleviated AS progression, while PARP1 overexpression exacerbated foam cell formation and lipophagy blockage. The above effects of PARP1 were weakened by PI3K inhibitor LY294002. PARP1 also inhibited the combination of the ABCG1 and PLIN1. ConclusionGeniposide alleviated AS by restoring PARP1/PI3K/AKT signaling pathway-suppressed lipophagy. This study is the first to present the lipophagy-inducing effect of Geniposide and the binding of ABCG1 and PLIN1 inhibited by PARP1.

Gut microbiome and metabolomic profiles reveal the antiatherosclerotic effect of indole-3-carbinol in high-choline-fed ApoE-/- mice

BackgroundThe metabolites produced from choline contribute to atherosclerosis (AS) pathogenesis, and the gut microbiota is redundantly essential for this process. Indole-3-carbinol (I3C), found in cruciferous vegetables such as broccoli, cabbage, cauliflower and brussels sprouts, helps prevent hyperlipidemia, maintain the gut microbiota balance, and decrease the production of trimethylamine-N-oxide (TMAO) from choline in the diet. PurposeThe objective of this research was to investigate the impact of I3C on choline-induced AS and to further elucidate the underlying mechanism involved. MethodsAS models of high-choline-induced ApoE-/- mice and TMAO-promoted foamy macrophages were established to observe the effect of I3C on the formation of atherosclerotic plaques and foam cells and changes in AS-related indicators (including blood biochemical indicators, TMA, TMAO, SRA, and SRB1), and integrated analyses of the microbiome and metabolome were used to reveal the mechanism of action of I3C. ResultsWe found that I3C inhibited high-choline-induced atheroma formation (50–100 mg/kg/d, in vivo) and slightly improved the lipid profile (15 mg/kg/d, in vivo). Moreover, I3C suppressed lipid influx at a concentration of 40 µmol/L in vitro, enhanced the diversity of the gut microbiota and the abundance of the phylum Verrucomicrobia, and consequently modified the gut microbial metabolites at a dosage of 50 mg/kg/d in the mice. Associative analyses based on microbiome and metabolomics revealed that 1-methyladenosine was a key modulator of the protective effect of I3C against AS in high-choline-induced ApoE-/- mice. ConclusionThese findings demonstrate for the first time that I3C ameliorates AS progression through remodeling of the gut microbiome and metabolomics, which paves the way for the possible therapeutic use of this vegetable-derived natural compound and may reduce the clinical severity of AS-related cardiovascular diseases.

SGLT2 Inhibitors Extra Glycemic Potential: A Possible Novel Approach to the Prevention of Atherosclerotic Events

Introduction: Cardiovascular diseases are a major global health concern, with atherosclerosis being a significant contributor. Diabetes mellitus is a well-known risk factor for atherosclerosis, and SGLT2 inhibitors are more effective in reducing cardiovascular disease and mortality compared to other antihyperglycemic agents in patients with type 2 diabetes. Endothelial dysfunction, VSMC phenotypic alterations, inflammation, autophagy, oxidative stress, signaling hormones and dysbiosis are crucial factors and predictors of atherosclerosis and other cardiovascular events. SGLT2 inhibitors have been shown to alleviate these components in atherosclerotic models. Material and Methods: To proceed we analyzed and took into account all publications, including clinical trials, animal studies, in vitro observations, reviews, and meta-analyses from various scientific databases. Results: Evidently, SGLT2i attenuate the progression of atherosclerosis by repressing vascular inflammation, oxidative stress, endothelial dysfunction, mitigating vascular smooth muscle cells function, impairing foam cell formation, preventing platelet activation and restoration of normal autophagic function. Conclusion: Based on these findings, it can be inferred that SGLT2 inhibitors exhibit anti-atherosclerotic characteristics and may have positive implications for the management of atherosclerosis, particularly in individuals with diabetic complications.

The Role of Fatty Acid Synthase in the Vascular Smooth Muscle Cell to Foam Cell Transition.

Vascular smooth muscle cells (VSMCs), in their contractile and differentiated state, are fundamental for maintaining vascular function. Upon exposure to cholesterol (CHO), VSMCs undergo dedifferentiation, adopting characteristics of foam cells-lipid-laden, macrophage-like cells pivotal in atherosclerotic plaque formation. CHO uptake by VSMCs leads to two primary pathways: ABCA1-mediated efflux or storage in lipid droplets as cholesterol esters (CEs). CE formation, involving the condensation of free CHO and fatty acids, is catalyzed by sterol O-acyltransferase 1 (SOAT1). The necessary fatty acids are synthesized by the lipogenic enzyme fatty acid synthase (FASN), which we found to be upregulated in atherosclerotic human coronary arteries. This observation led us to hypothesize that FASN-mediated fatty acid biosynthesis is crucial in the transformation of VSMCs into foam cells. Our study reveals that CHO treatment upregulates FASN in human aortic SMCs, concurrent with increased expression of CD68 and upregulation of KLF4, markers associated with the foam cell transition. Crucially, downregulation of FASN inhibits the CHO-induced upregulation of CD68 and KLF4 in VSMCs. Additionally, FASN-deficient VSMCs exhibit hindered lipid accumulation and an impaired transition to the foam cell phenotype following CHO exposure, while the addition of the fatty acid palmitate, the main FASN product, exacerbates this transition. FASN-deficient cells also show decreased SOAT1 expression and elevated ABCA1. Notably, similar effects are observed in KLF4-deficient cells. Our findings demonstrate that FASN plays an essential role in the CHO-induced upregulation of KLF4 and the VSMC to foam cell transition and suggest that targeting FASN could be a novel therapeutic strategy to regulate VSMC phenotypic modulation.

Development and modeling of an ultra-robust TPU-MWCNT foam with high flexibility and compressibility

Abstract Developing a cost-effective industrially scalable manufacturing method that can improve the mechanical properties of nanocomposite foams with higher flexibility, compressibility, and, at the same time, mechanically robustness is of significant interest. In this study, porous thermoplastic polyurethane (TPU)/multiwalled carbon nanotube (MWCNT) was fabricated with the chemical blowing agent (CBA) by a combination of compounding-compression molding methods. The effects of CBA and MWCNT contents on the foam morphology, porosity, foam cell size, Young’s modulus, and compressibility of fabricated samples were investigated. Through conducting cyclic compressive tests, it was observed that nanocomposite foams exhibited consistent mechanical responses across multiple compressive cycles and demonstrated notable characteristics, including high compressibility (up to 76.4% compressive strain) and high elastic modulus (up to 8.8 ± 2.6 MPa). Moreover, theoretical approaches were employed to predict the elastic modulus of solid and foam TPU/MWCNT. For solid MWCNT/TPU, a specific micromechanical model based on different modifications of the Halpin-Tsai (HT) approach was used, which showed a good agreement with experimental data at different MWCNT contents. Furthermore, the constant parameters of Gibson and Ashby’s method were found to successfully predict the elastic modulus of foam TPU/MWCNT at different MWCNT and CBA percentages.

Foam Cells Analysis from Retrieved Stroke Clot for the Identification of Atherothrombotic Etiology

Background: In atherothrombotic acute ischemic stroke (AIS), when the atheroma breaks down, the clot can incorporate foam cells (FCs). The identification of the correct etiology is paramount for secondary stroke prevention. This study aims to evaluate the presence of the FC in the arterial clot, and to determine whether patients with FCs and patients without FCs (NFCs) had different cerebrovascular risk factors, haemato-chemical parameters, and atherosclerotic disease incidence, in order to predict the etiological diagnosis. Methods: We collected 100 clots retrieved by mechanical thrombectomy from 495 consecutive AIS patients with large vessel occlusion. An expert pathologist evaluated the FC presence by histological examination stained with hematoxylin and eosin. Results: We observed FCs in 29/100 (29%) of retrieved clots and divided the patients into two groups, with/without FCs. The two groups had similar clinical and laboratory features, with a discrepancy between the FC presence in the clot and the clinical etiological diagnosis, even if not statistically significant. Conclusions: Our study showed the presence of FCs in approximately one-third of the retrieved clots, but the identification of the clot that presumably comes from the atheromatous plaque rupture tended to disagree with the clinical diagnosis. Future studies may reveal their potential to disclose clot origin or specific patient characteristics, guiding treatment options.

Modulation of atherosclerosis-related signaling pathways by Chinese herbal extracts: Recent evidence and perspectives.

Atherosclerotic cardiovascular disease remains a preeminent cause of morbidity and mortality globally. The onset of atherosclerosis underpins the emergence of ischemic cardiovascular diseases, including coronary heart disease (CHD). Its pathogenesis entails multiple factors such as inflammation, oxidative stress, apoptosis, vascular endothelial damage, foam cell formation, and platelet activation. Furthermore, it triggers the activation of diverse signaling pathways including Phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), NF-E2-related factor 2/antioxidant response element (Nrf2/ARE), the Notch signaling pathway, peroxisome proliferator-activated receptor (PPAR), nucleotide oligo-structural domain-like receptor thermoprotein structural domain-associated protein 3 (NLRP3), silencing information regulator 2-associated enzyme 1 (Sirt1), nuclear transcription factor-κB (NF-κB), Circular RNA (Circ RNA), MicroRNA (mi RNA), Transforming growth factor-β (TGF-β), and Janus kinase-signal transducer and activator of transcription (JAK/STAT). Over recent decades, therapeutic approaches for atherosclerosis have been dominated by the utilization of high-intensity statins to reduce lipid levels, despite significant adverse effects. Consequently, there is a growing interest in the development of safer and more efficacious drugs and therapeutic modalities. Traditional Chinese medicine (TCM) offers a vital strategy for the prevention and treatment of cardiovascular diseases. Numerous studies have detailed the mechanisms through which TCM active ingredients modulate signaling molecules and influence the atherosclerotic process. This article reviews the signaling pathways implicated in the pathogenesis of atherosclerosis and the advancements in research on TCM extracts for prevention and treatment, drawing on original articles from various databases including Google Scholar, Medline, CNKI, Scopus, and Pubmed. The objective is to furnish a reference for the clinical management of cardiovascular diseases.

Biomechanics-mediated endocytosis in atherosclerosis.

Biomechanical forces, including vascular shear stress, cyclic stretching, and extracellular matrix stiffness, which influence mechanosensitive channels in the plasma membrane, determine cell function in atherosclerosis. Being highly associated with the formation of atherosclerotic plaques, endocytosis is the key point in molecule and macromolecule trafficking, which plays an important role in lipid transportation. The process of endocytosis relies on the mobility and tension of the plasma membrane, which is sensitive to biomechanical forces. Several studies have advanced the signal transduction between endocytosis and biomechanics to elaborate the developmental role of atherosclerosis. Meanwhile, increased plaque growth also results in changes in the structure, composition and morphology of the coronary artery that contribute to the alteration of arterial biomechanics. These cross-links of biomechanics and endocytosis in atherosclerotic plaques play an important role in cell function, such as cell phenotype switching, foam cell formation, and lipoprotein transportation. We propose that biomechanical force activates the endocytosis of vascular cells and plays an important role in the development of atherosclerosis.