Search Results (47)

Background: Aortic stenosis (AS) has long been considered a degenerative disease and is typically diagnosed in older men at an advanced stage. However, accumulating evidence has highlighted the similarities between AS and atherosclerosis, particularly regarding shared risk factors and overlapping pathophysiological mechanisms. This connection has led to a paradigm shift, suggesting that AS may be preventable in its early stages. Methods: This narrative review synthesizes the existing literature exploring the parallels between AS and atherosclerosis, focusing on common risk factors, pathogenic pathways, and evolving therapeutic strategies. Clinical trials and translational studies were examined to assess the effectiveness of atherosclerosis-based treatments for AS. Results: Multiple studies have confirmed the shared inflammatory, lipid-mediated, and calcific mechanisms of AS and atherosclerosis. Despite these similarities, therapeutic strategies effective in atherosclerosis, such as statin therapy, have not consistently shown benefits in AS. New medical approaches aim to delay aortic valve replacement and reduce the associated morbidity. The partially overlapping pathogenesis continues to guide future research. Conclusions: While AS and atherosclerosis share several pathogenic features, their clinical courses and treatment responses diverge. Understanding the limits and potential of their overlap may inform future preventive and therapeutic strategies. Earlier detection and targeted intervention in AS remain key goals, drawing on insights from cardiovascular disease management. Full article

Artemisia absinthium L. contributes to ecological stabilization in arid regions through its deep root system for sand fixation and soil microenvironment modulation, thereby effectively mitigating desertification. Total terpenoids have been extracted from A. absinthium (AATP) and found to have antioxidant and anti-inflammatory activities. Terpenoids are a class of natural products derived from methyl hydroxypropanoic acid, for which their structural units consist of multiple isoprene (C5) units. They are one of the largest and most structurally diverse classes of natural compounds. However, there are still large gaps in knowledge regarding their exact biological activities and effects. Atherosclerosis (AS) is a prevalent cardiovascular disease marked by the chronic inflammation of the vascular system, and lipid metabolism plays a key role in its pathogenesis. This study determined the extraction and purification processes of AATP through single-factor experiments and response surface optimization methods. The purity of AATP was increased from 20.85% ± 0.94 before purification to 52.21% ± 0.75, which is 2.5 times higher than before purification. Studies have shown that the total terpenoids of A. absinthium significantly reduced four indices of serum lipids in atherosclerosis (AS) rats, thereby promoting lipid metabolism, inhibiting inflammatory processes, and hindering aortic wall thickening and hepatic fat accumulation. It is known from network pharmacology studies that AATP regulates the Janus kinase/signal transducer (JAK/STAT) signaling axis. Molecular docking studies have indicated that the active component of AATP effectively binds to Janus kinase (JAK2) and signal transducer (STAT3) target proteins. The results indicate that AATP can inhibit the release of pro-inflammatory mediators (such as reactive oxygen species (ROS)) in LPS-induced RAW264.7 macrophages. It also inhibits the M1 polarization of RAW264.7 macrophages. Protein immunoblotting analysis revealed that it significantly reduces the phosphorylation levels of Janus kinase (JAK2) and the signal transducer and activator of transcription 3 (STAT3). Research indicates that the active components in A. absinthium may exert anti-atherosclerotic effects by regulating lipid metabolism and inhibiting inflammatory responses. It holds potential value for development as a functional food or drug for the prevention and treatment of atherosclerosis. Full article

Atherosclerosis, which has important effects on the development of cardiovascular diseases, is a widespread health problem with the highest mortality rate globally. In this study, we aimed to assess the impact of water and ethanolic extracts of propolis on oxidized low-density lipoprotein (OxLDL) and lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in the progression of the atherosclerotic process, which is characterized by oxidative stress, inflammation, and dyslipidemia. In our study, apolipoprotein E knockout (ApoE^−/−) and C57BL/6J mice were used as study groups. Water (WEP) and ethanolic extracts (EEP) of propolis were administered intraperitoneally to ApoE^−/− and C57BL/6J mice modeled with a high-fat diet. Under anesthesia, the animals were euthanized by decapitation, and serum, along with aortic tissues, was collected. Serum total cholesterol (TC), triglyceride (TG), OxLDL and LOX-1 levels, OxLDL levels in aortic tissue homogenate, and subendothelial lipid accumulation levels by histological staining were determined in mice and statistical analyses were performed. WEP and EEP supplementation significantly decreased serum TC, TG, OxLDL, LOX-1, and tissue OxLDL levels and reduced plaque burden in the aortic root, with statistically significant differences observed. Those results suggest that propolis extracts have a potential treatment option for atherosclerosis, as a food supplement or a complementary medical/functional food. However, further research is needed to elucidate their molecular mechanisms, evaluate clinical efficacy and safety, and explore possible synergistic effects with existing atherosclerosis treatments. Full article

Atherosclerosis, a leading contributor to cardiovascular diseases (CVDs), is characterized by foam cell formation driven by excessive lipid accumulation in macrophages and vascular smooth muscle cells. This study elucidates the anti-atherosclerotic potential of AWLNH (P3) and PHDL (P4) peptides by assessing their effects on foam cell formation, lipid metabolism, and oxidative stress regulation. P3 and P4 effectively suppressed intracellular lipid accumulation in RAW264.7 macrophages and human aortic smooth muscle cells (hASMCs), thereby mitigating foam cell formation. Mechanistically, both peptides modulated cholesterol homeostasis by downregulating cholesterol influx mediators, cluster of differentiation 36 (CD36), and class A1 scavenger receptor (SR-A1), while upregulating cholesterol efflux transporters ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1). The activation of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further substantiated their role in promoting cholesterol efflux and restoring lipid homeostasis. Additionally, P3 and P4 peptides exhibited potent antioxidative properties by attenuating reactive oxygen species (ROS) generation through activation of the HO-1/Nrf2 signaling axis. HO-1 silencing via siRNA transfection abolished these effects, confirming HO-1-dependent regulation of oxidative stress and lipid metabolism. Collectively, these findings highlight P3 and P4 peptides as promising therapeutic agents for atherosclerosis by concurrently targeting foam cell formation, cholesterol dysregulation, and oxidative stress, warranting further exploration for potential clinical applications. Full article

Background: Atherosclerosis, a persistent inflammatory disease marked by the presence of atherosclerotic plaques or fibrous plaques, is a significant contributor to the onset of the development of cardiovascular disease. Tremella fuciformis Berk contains various active ingredients that have anti-inflammatory, antioxidant, and hypolipidemic properties. Nevertheless, the potential effects of T. fuciformis on atherosclerosis have not been systematically reported. Method: In this study, ApoE^−/− mice were employed as models of atherosclerosis caused by a high-fat diet (HFD) to investigate the effect of T. fuciformis. Gut microbiota and serum metabolism analysis were performed to elucidate the potential mechanism of T. fuciformis for its anti-atherosclerosis effects. Results: T. fuciformis significantly decreased the aortic root wall thickness and the area of lipid droplets, regulated lipid levels, and inhibited fat accumulation to improve aortic root lesions. Furthermore, T. fuciformis significantly altered serum metabolite (including diethyl phthalate and succinate) levels, regulated the abundance of microbiota, such as Coriobacteriaceae_UCG-002 and Alistipes, and suppressed the inflammatory response to ameliorate atherosclerosis via the nuclear factor-kappa B (NF-κB)-mediated inflammatory response in HFD-induced ApoE^−/− mice. Conclusions: These results offer a theoretical basis and data to support T. fuciformis as a potential strategy for treating atherosclerosis. Full article

Clinical and genetic studies strongly support a significant connection between nonalcoholic fatty liver disease (NAFLD) and atherosclerotic cardiovascular disease (ASCVD) and identify ASCVD as the primary cause of death in NAFLD patients. Understanding the molecular factors and mechanisms regulating these diseases is critical for developing novel therapies that target them simultaneously. Our preliminary immunoblotting experiments demonstrated elevated expression of nidogen 2 (NID2), a basement membrane glycoprotein, in human atherosclerotic vascular tissues and murine steatotic livers. Therefore, we investigated the role of NID2 in regulating hepatosteatosis and atherosclerosis utilizing Western diet-fed Apoe^−/− mice with/without NID2 overexpression. Quantitative real-time PCR confirmed increased NID2 mRNA expression in multiple organs (liver, heart, kidney, and adipose) of NID2-overexpressing mice. Male mice with NID2 overexpression exhibited higher liver and epididymal white adipose tissue mass, increased hepatic lipid accumulation, and fibrosis. Additionally, these mice developed larger atherosclerotic lesions in the whole aortas and aortic roots, with increased necrotic core formation. Mechanistic studies showed reduced AMPK activation in the livers of NID2-overexpressing mice compared with controls, without any effects on hepatic inflammation. In conclusion, these findings suggest that NID2 plays a deleterious role in both hepatosteatosis and atherosclerosis, making it a potential therapeutic target for these conditions. Full article

Atherosclerosis is a key etiological event in the development of cardiovascular diseases (CVDs), strongly linked to the formation of foam cells. This study explored the effects of two blue mussel-derived bioactive peptides (BAPs), PIISVYWK (P1) and FSVVPSPK (P2), on inhibiting foam cell formation and mitigating inflammation in oxLDL-treated RAW264.7 macrophages. Both peptides significantly suppressed intracellular lipid accumulation and cholesterol levels while promoting cholesterol efflux by downregulating cluster of differentiation 36 (CD36) and class A1 scavenger receptors (SR-A1) and upregulating ATP binding cassette subfamily A member 1 (ABCA-1) and ATP binding cassette subfamily G member 1 (ABCG-1) expressions. The increased expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α) further validated their role in enhancing cholesterol efflux. Additionally, P1 and P2 inhibited foam cell formation in oxLDL-treated human aortic smooth muscle cells and exerted anti-inflammatory effects by reducing pro-inflammatory cytokines, nitric oxide (NO), prostaglandin E₂ (PGE₂), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2), primarily through inhibiting NF-κB activation. Furthermore, P1 and P2 alleviated oxidative stress by activating the Nrf2/HO-1 pathway. Our findings demonstrate that P1 and P2 have significant potential in reducing foam cell formation and inflammation, both critical factors in atherosclerosis development. These peptides may serve as promising therapeutic agents for the prevention and treatment of CVDs associated with oxidative stress and inflammation. Full article

The objective of this study was to elucidate the protective role of quercetin in atherosclerosis by examining its effect on the phenotypic switch of vascular smooth muscle cells (VSMCs) to macrophage-like cells and the underlying regulatory pathways. Aorta tissues from apolipoprotein E-deficient (ApoE KO) mice fed a high-fat diet (HFD), treated with or without 100 mg/kg/day quercetin, were analyzed for histopathological changes and molecular mechanisms. Quercetin was found to decrease the size of atherosclerotic lesions and mitigate lipid accumulation induced by HFD. Fluorescence co-localization analysis revealed a higher presence of macrophage-like vascular smooth muscle cells (VSMCs) co-localizing with phospho-Janus kinase 2 (p-JAK2), phospho-signal transducer and activator of transcription 3 (p-STAT3), and Krüppel-like factor 4 (KLF4) in regions of foam cell aggregation within aortic plaques. However, this co-localization was reduced following treatment with quercetin. Quercetin treatment effectively inhibited the KLF4-mediated phenotypic switch in oxidized low-density lipoprotein (ox-LDL)-loaded mouse aortic vascular smooth muscle cells (MOVAS), as indicated by decreased expressions of KLF4, LGALS3, CD68, and F4/80, increased expression of alpha smooth muscle actin (α-SMA), reduced intracellular fluorescence Dil-ox-LDL uptake, and decreased lipid accumulation. In contrast, APTO-253, a KLF4 activator, was found to reverse the effects of quercetin. Furthermore, AG490, a JAK2 inhibitor, effectively counteracted the ox-LDL-induced JAK2/STAT3 pathway-dependent switch to a macrophage-like phenotype and lipid accumulation in MOVAS cells. These effects were significantly mitigated by quercetin but exacerbated by coumermycin A1, a JAK2 activator. Our research illustrates that quercetin inhibits the KLF4-mediated phenotypic switch of VSMCs to macrophage-like cells and reduces atherosclerosis by suppressing the JAK2/STAT3 pathway. Full article

Abdominal aortic aneurysm (AAA) is a chronic aortic disease that lacks effective pharmacological therapies. This study was performed to determine the influence of treatment with the gasdermin D inhibitor necrosulfonamide on experimental AAAs. AAAs were induced in male apolipoprotein E-deficient mice by subcutaneous angiotensin II infusion (1000 ng/kg body weight/min), with daily administration of necrosulfonamide (5 mg/kg body weight) or vehicle starting 3 days prior to angiotensin II infusion for 30 days. Necrosulfonamide treatment remarkably suppressed AAA enlargement, as indicated by reduced suprarenal maximal external diameter and surface area, and lowered the incidence and reduced the severity of experimental AAAs. Histologically, necrosulfonamide treatment attenuated medial elastin breaks, smooth muscle cell depletion, and aortic wall collagen deposition. Macrophages, CD4⁺ T cells, CD8⁺ T cells, and neovessels were reduced in the aneurysmal aortas of necrosulfonamide- as compared to vehicle-treated angiotensin II-infused mice. Atherosclerosis and intimal macrophages were also substantially reduced in suprarenal aortas from angiotensin II-infused mice following necrosulfonamide treatment. Additionally, the levels of serum interleukin-1β and interleukin-18 were significantly lower in necrosulfonamide- than in vehicle-treated mice without affecting body weight gain, lipid levels, or blood pressure. Our findings indicate that necrosulfonamide reduced experimental AAAs by preserving aortic structural integrity as well as reducing mural leukocyte accumulation, neovessel formation, and systemic levels of interleukin-1β and interleukin-18. Thus, pharmacologically inhibiting gasdermin D activity may lead to the establishment of nonsurgical therapies for clinical AAA disease. Full article

Atherosclerosis is one of the most important causes of cardiovascular diseases. A disintegrin and metalloprotease (ADAM)10 and ADAM17 have been identified as important regulators of inflammation in recent years. Our study investigated the effect of inhibiting these enzymes with selective inhibitor and propolis on atherosclerosis. In our study, C57BL/6J mice (n = 16) were used in the control and sham groups. In contrast, ApoE^-/- mice (n = 48) were used in the case, water extract of propolis (WEP), ethanolic extract of propolis (EEP), GW280264X (GW-synthetic inhibitor), and solvent (DMSO and ethanol) groups. The control group was fed a control diet, and all other groups were fed a high-cholesterol diet for 16 weeks. WEP (400 mg/kg/day), EEP (200 mg/kg/day), and GW (100 µg/kg/day) were administered intraperitoneally for the last four weeks. Animals were sacrificed, and blood, liver, aortic arch, and aortic root tissues were collected. In serum, total cholesterol (TC), triglycerides (TGs), and glucose (Glu) were measured by enzymatic colorimetric method, while interleukin-1β (IL-1β), paraoxonase-1 (PON-1), and lipoprotein-associated phospholipase-A2 (Lp-PLA2) were measured by ELISA. Tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), myeloperoxidase (MPO), interleukin-6 (IL-6), interleukin-10 (IL-10), and interleukin-12 (IL-12) levels were measured in aortic arch by ELISA and ADAM10/17 activities were measured fluorometrically. In addition, aortic root and liver tissues were examined histopathologically and immunohistochemically (ADAM10 and sortilin primary antibody). In the WEP, EEP, and GW groups compared to the case group, TC, TG, TNF-α, IL-1β, IL-6, IL-12, PLA2, MPO, ADAM10/17 activities, plaque burden, lipid accumulation, ADAM10, and sortilin levels decreased, while IL-10 and PON-1 levels increased (p < 0.003). Our study results show that propolis can effectively reduce atherosclerosis-related inflammation and dyslipidemia through ADAM10/17 inhibition. Full article

Atherosclerosis is closely associated with metabolic disorders such as cholesterol accumulation, bile acid metabolism, and gut dysbiosis. Neoagarotetraose supplementation has been shown to inhibit obesity and alleviate type 2 diabetes, but its effects on modulating the development of atherosclerosis remain unexplored. Therefore, the present study was conducted to investigate the protective effects and potential mechanisms of neoagarotetraose on high-fat, high-cholesterol diet (HFHCD)-induced atherosclerosis in ApoE^−/− mice. The results showed that neoagarotetraose supplementation decreased the atherosclerotic lesion area by 50.1% and the aortic arch lesion size by 80.4% compared to the HFHCD group. Furthermore, neoagarotetraose supplementation led to a significant reduction in hepatic lipid content, particularly non-high-density lipoprotein cholesterol. It also resulted in a substantial increase in total bile acid content in both urine and fecal samples by 3.0-fold and 38.7%, respectively. Moreover, neoagarotetraose supplementation effectively downregulated the intestinal farnesoid X receptor by 35.8% and modulated the expressions of its associated genes in both the liver and intestine. In addition, correlation analysis revealed strong associations between gut microbiota composition and fecal bile acid levels. These findings highlight the role of gut microbiota in neoagarotetraose-mitigating atherosclerosis in HFHCD-fed ApoE^−/− mice. This study indicates the potential of neoagarotetraose as a functional dietary supplement for the prevention of atherosclerosis. Full article

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. Full article

Atherosclerosis and resulting cardiovascular disease are the leading causes of death in the US. Hyperhomocysteinemia (HHcy), or the accumulation of the intermediate amino acid homocysteine, is an independent risk factor for atherosclerosis, but the intricate biological processes mediating this effect remain elusive. Several factors regulate homocysteine levels, including the activity of several enzymes and adequate levels of their coenzymes, including pyridoxal phosphate (vitamin B6), folate (vitamin B9), and methylcobalamin (vitamin B12). To better understand the biological influence of HHcy on the development and progression of atherosclerosis, apolipoprotein-E-deficient (apoE^−/− mice), a model for human atherosclerosis, were fed a hyperhomocysteinemic diet (low in methyl donors and B vitamins) (HHD) or a control diet (CD). After eight weeks, the plasma, aorta, and liver were collected to quantify methylation metabolites, while plasma was also used for a broad targeted metabolomic analysis. Aortic plaque burden in the brachiocephalic artery (BCA) was quantified via 14T magnetic resonance imaging (MRI). A severe accumulation of plasma and hepatic homocysteine and an increased BCA plaque burden were observed, thus confirming the atherogenic effect of the HHD. Moreover, a decreased methylation capacity in the plasma and aorta, indirectly assessed by the ratio of S-adenosylmethionine to S-adenosylhomocysteine (SAM:SAH) was detected in HHD mice together with a 172-fold increase in aortic cystathionine levels, indicating increased flux through the transsulfuration pathway. Betaine and its metabolic precursor, choline, were significantly decreased in the livers of HHD mice versus CD mice. Widespread changes in the plasma metabolome of HHD mice versus CD animals were detected, including alterations in acylcarnitines, amino acids, bile acids, ceramides, sphingomyelins, triacylglycerol levels, and several indicators of dysfunctional lipid metabolism. This study confirms the relevance of severe HHcy in the progression of vascular plaque and suggests novel metabolic pathways implicated in the pathophysiology of atherosclerosis. Full article

Apolipoprotein E-knockout (Apoe-/-) mice constitute the most widely employed animal model of atherosclerosis. Deletion of Apoe induces profound hypercholesterolemia and promotes the development of atherosclerosis. However, despite its widespread use, the Apoe-/- mouse model remains incompletely characterized, especially at late time points and advanced disease stages. Thus, it is unclear how late atherosclerotic plaques compare to earlier ones in terms of lipid deposition, calcification, macrophage accumulation, smooth muscle cell presence, or plaque necrosis. Additionally, it is unknown how cardiac function and hemodynamic parameters are affected at late disease stages. Here, we used a comprehensive analysis based on histology, fluorescence microscopy, and Doppler ultrasonography to show that in normal chow diet-fed Apoe-/- mice, atherosclerotic lesions at the level of the aortic valve evolve from a more cellular macrophage-rich phenotype at 26 weeks to an acellular, lipid-rich, and more necrotic phenotype at 52 weeks of age, also marked by enhanced lipid deposition and calcification. Coronary artery atherosclerotic lesions are sparse at 26 weeks but ubiquitous and extensive at 52 weeks; yet, left ventricular function was not significantly affected. These findings demonstrate that atherosclerosis in Apoe-/- mice is a highly dynamic process, with atherosclerotic plaques evolving over time. At late disease stages, histopathological characteristics of increased plaque vulnerability predominate in combination with frequent and extensive coronary artery lesions, which nevertheless may not necessarily result in impaired cardiac function. Full article

The hormone adiponectin has many beneficial effects in atherosclerosis, as gene deficiency in adiponectin or its receptor has shown detrimental effects on plaque burden in mice. Our objective was to understand the potential roles adiponectin deficiency has on aortic plaque content, inflammation, and markers of cardiovascular disease according to sex and age. To study the influence of adiponectin status on sex and atherosclerosis, we used young male and female adipoq^−/−apoe^−/−, adipoq^+/−apoe^−/−, and apoe^−/− mice, which were given a high-fat diet (HFD). Even a 50% reduction in the expression of adiponectin led to a plaque reduction in males and an increase in females compared with apoe^−/− controls. Changes in plaque were not attributed to changes in cholesterol or cardiovascular disease markers but correlated with inflammatory markers. Plaque reduction in males was associated with reduced monocyte chemoattractant protein 1 (MCP1) and increased colony stimulating factor 3 (CSF3), while the increase in plaque in females correlated with the opposite effect in these markers. In old mice, both adiponectin-deficient genotypes and sexes accumulated more plaque than their respective apoe^−/− controls. The increase in plaque with adiponectin deficiency according to age was not explained by a worsening lipid profile but correlated with increased levels of C-C motif chemokine ligand 5 (CCL5). Overall, our study uncovered genotype-specific effects that differed by sex and age of adiponectin deficiency in atherosclerosis. Full article