Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 1.206
Filter
1.
Front Immunol ; 15: 1364161, 2024.
Article in English | MEDLINE | ID: mdl-38803504

ABSTRACT

Introduction: Atherosclerosis, a leading cause of global cardiovascular mortality, is characterized by chronic inflammation. Central to this process is the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome, which significantly influences atherosclerotic progression. Recent research has identified that the olfactory receptor 2 (Olfr2) in vascular macrophages is instrumental in driving atherosclerosis through NLRP3- dependent IL-1 production. Methods: To investigate the effects of Corilagin, noted for its anti-inflammatory attributes, on atherosclerotic development and the Olfr2 signaling pathway, our study employed an atherosclerosis model in ApoE-/- mice, fed a high-fat, high-cholesterol diet, alongside cellular models in Ana-1 cells and mouse bone marrow-derived macrophages, stimulated with lipopolysaccharides and oxidized low-density lipoprotein. Results: The vivo and vitro experiments indicated that Corilagin could effectively reduce serum lipid levels, alleviate aortic pathological changes, and decrease intimal lipid deposition. Additionally, as results showed, Corilagin was able to cut down expressions of molecules associated with the Olfr2 signaling pathway. Discussion: Our findings indicated that Corilagin effectively inhibited NLRP3 inflammasome activation, consequently diminishing inflammation, macrophage polarization, and pyroptosis in the mouse aorta and cellular models via the Olfr2 pathway. This suggests a novel therapeutic mechanism of Corilagin in the treatment of atherosclerosis.


Subject(s)
Atherosclerosis , Glucosides , Hydrolyzable Tannins , Inflammasomes , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein , Signal Transduction , Animals , Hydrolyzable Tannins/pharmacology , Hydrolyzable Tannins/therapeutic use , NLR Family, Pyrin Domain-Containing 3 Protein/metabolism , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Mice , Signal Transduction/drug effects , Inflammasomes/metabolism , Glucosides/pharmacology , Glucosides/therapeutic use , Macrophages/metabolism , Macrophages/immunology , Macrophages/drug effects , Male , Disease Models, Animal , Mice, Inbred C57BL , Mice, Knockout, ApoE
2.
Phytomedicine ; 129: 155662, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38728917

ABSTRACT

BACKGROUND: Naoxintong capsule (NXT) is a compound traditional Chinese medicine prescription with demonstrated effect for the treatment of cardiovascular and cerebrovascular diseases including atherosclerosis (AS). However, the pharmacological mechanisms of NXT in ameliorating early-stage AS are still unclear, especially regarding the role of gut microbiota. PURPOSE: This study is aiming to evaluate the therapeutic effect of NXT against early-stage AS, and further illustrate the potential correlations among AS, gut microbiota, and NXT. METHODS: Thirty-two male ApoE knockout mice (C57BL/6 background) were fed with a high cholesterol diet (HCD) for 4 weeks to establish an early-stage AS model. NXT in two different dosages and simvastatin (Simv) were than administrated for another 8 weeks. Lipid metabolism indicators and inflammation levels were measured with corresponding assay kits. Changes in blood vessels, liver lesions, and intestinal barrier proteins were evaluated with different staining methods. Furthermore, the gut microbiota structure was analyzed using 16S rRNA sequencing technology, while GC-MS was utilized to determine the fecal contents of short-chain fatty acids (SCFAs). RESULTS: Administration of NXT significantly ameliorated obesity, hyperlipidemia, systemic inflammation, vasculopathy, liver injury, and intestinal barrier disorder in AS mice. Administration of NXT also significantly regulated the gut microbiota disturbance and increased the total contents of fecal SCFAs in AS mice. Furthermore, acetic acid content and the relative abundance of Faecalibacterium in feces were proposed as potential therapeutic biomarkers of NXT for AS treatment as indicated via the correlation analysis. CONCLUSION: This study demonstrated that NXT could effectively treat early-stage AS induced by HCD in mice. NXT regulated the gut microbiota and metabolites, maintained intestinal homeostasis, and improved the systemic inflammatory response. These findings may provide robust experimental support for the clinical use of NXT for AS treatment.


Subject(s)
Atherosclerosis , Drugs, Chinese Herbal , Gastrointestinal Microbiome , Mice, Inbred C57BL , Animals , Gastrointestinal Microbiome/drug effects , Drugs, Chinese Herbal/pharmacology , Male , Atherosclerosis/drug therapy , Mice , Apolipoproteins E , Mice, Knockout, ApoE , Lipid Metabolism/drug effects , Fatty Acids, Volatile/metabolism , Disease Models, Animal , Capsules , Diet, High-Fat , Simvastatin/pharmacology
3.
Biochem Pharmacol ; 225: 116314, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38797271

ABSTRACT

Atherosclerosis, a chronic inflammatory disease, is the most relevant cause of carotid artery stenosis. Vascular endothelial cells (ECs) play a significant role in the development of atherosclerosis. In this chronic inflammatory environment, we aimed to investigate whether PCSK9 could mitigate atherosclerosis progression by reducing tissue factor expression in ECs via in vivo and in vitro assays. In vivo, we investigated the effect of PCSK9 inhibition on preventing atherosclerotic lesion formation in ApoE-/- mice fed a western diet. The results showed that inhibiting PCSK9 could significantly downregulate the protein expression of tissue factor (TF) in ECs to reduce the area of atherosclerotic plaques. In vitro, we incubated human umbilical vein endothelial cells (HUVECs) with lipopolysaccharide (LPS). We found that LPS-induced TF elevation was suppressed by a PCSK9 inhibitor at both the mRNA and protein levels and that the TLR4/NF-κB pathway was also suppressed by a PCSK9 inhibitor. With respect to plasma samples from patients with carotid artery stenosis, we also demonstrated that the expression of TF was positively correlated with that of PCSK9. Thus, in addition to regulating lipid metabolism, the regulation of endothelial cell TF expression through the TLR4/NF-κB pathway may be a potential mechanism of PCSK9 in promoting atherosclerotic carotid stenosis.


Subject(s)
Apolipoproteins E , Carotid Stenosis , Human Umbilical Vein Endothelial Cells , Mice, Inbred C57BL , NF-kappa B , Proprotein Convertase 9 , Signal Transduction , Thromboplastin , Toll-Like Receptor 4 , Animals , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/genetics , Mice , NF-kappa B/metabolism , Proprotein Convertase 9/genetics , Proprotein Convertase 9/metabolism , Humans , Carotid Stenosis/metabolism , Male , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Apolipoproteins E/deficiency , Human Umbilical Vein Endothelial Cells/metabolism , Thromboplastin/metabolism , Thromboplastin/genetics , Thromboplastin/biosynthesis , Signal Transduction/physiology , Mice, Knockout, ApoE , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Mice, Knockout , PCSK9 Inhibitors , Female
4.
Arterioscler Thromb Vasc Biol ; 44(6): 1379-1392, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38695167

ABSTRACT

BACKGROUND: Thromboembolic events secondary to rupture or erosion of advanced atherosclerotic lesions is the global leading cause of death. The most common and effective means to reduce these major adverse cardiovascular events, including myocardial infarction and stroke, is aggressive lipid lowering via a combination of drugs and dietary modifications. However, we know little regarding the effects of reducing dietary lipids on the composition and stability of advanced atherosclerotic lesions, the mechanisms that regulate these processes, and what therapeutic approaches might augment the benefits of lipid lowering. METHODS: Smooth muscle cell lineage-tracing Apoe-/- mice were fed a high-cholesterol Western diet for 18 weeks and then a zero-cholesterol standard laboratory diet for 12 weeks before treating them with an IL (interleukin)-1ß or control antibody for 8 weeks. We assessed lesion size and remodeling indices, as well as the cellular composition of aortic and brachiocephalic artery lesions, indices of plaque stability, overall plaque burden, and phenotypic transitions of smooth muscle cell and other lesion cells by smooth muscle cell lineage tracing combined with single-cell RNA sequencing, cytometry by time-of-flight, and immunostaining plus high-resolution confocal microscopic z-stack analysis. RESULTS: Lipid lowering by switching Apoe-/- mice from a Western diet to a standard laboratory diet reduced LDL cholesterol levels by 70% and resulted in multiple beneficial effects including reduced overall aortic plaque burden, as well as reduced intraplaque hemorrhage and necrotic core area. However, contrary to expectations, IL-1ß antibody treatment after diet-induced reductions in lipids resulted in multiple detrimental changes including increased plaque burden and brachiocephalic artery lesion size, as well as increasedintraplaque hemorrhage, necrotic core area, and senescence as compared with IgG control antibody-treated mice. Furthermore, IL-1ß antibody treatment upregulated neutrophil degranulation pathways but downregulated smooth muscle cell extracellular matrix pathways likely important for the protective fibrous cap. CONCLUSIONS: Taken together, IL-1ß appears to be required for the maintenance of standard laboratory diet-induced reductions in plaque burden and increases in multiple indices of plaque stability.


Subject(s)
Atherosclerosis , Disease Models, Animal , Interleukin-1beta , Mice, Knockout, ApoE , Myocytes, Smooth Muscle , Plaque, Atherosclerotic , Animals , Interleukin-1beta/metabolism , Atherosclerosis/pathology , Atherosclerosis/prevention & control , Atherosclerosis/metabolism , Atherosclerosis/genetics , Mice , Myocytes, Smooth Muscle/pathology , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/drug effects , Male , Diet, Western , Mice, Inbred C57BL , Aorta/pathology , Aorta/metabolism , Aorta/drug effects , Aortic Diseases/pathology , Aortic Diseases/prevention & control , Aortic Diseases/genetics , Aortic Diseases/metabolism , Diet, High-Fat , Muscle, Smooth, Vascular/pathology , Muscle, Smooth, Vascular/metabolism , Muscle, Smooth, Vascular/drug effects , Brachiocephalic Trunk/pathology , Brachiocephalic Trunk/metabolism , Brachiocephalic Trunk/drug effects
5.
Article in English | MEDLINE | ID: mdl-38780292

ABSTRACT

ABSTRACT: Arteriosclerosis (AS) is a chronic inflammatory disease and Buyang Huanwu decoction (BHD) has been identified as an anti-atherosclerosis effect, and the study is aimed to investigate the underlying mechanism. The E4 allele of Apolipoprotein E (ApoE) is associated with both metabolic dysfunction and an enhanced pro-inflammatory response, ApoE-knockout (ApoE-/-) mice were fed with a high-fat diet to establish an arteriosclerosis model and treated with BHD or atorvastatin (as a positive control). The atherosclerotic plaque in each mouse was evaluated using Oil red O Staining. Elisa kits were used to evaluate blood lipid, interleukin-6 (IL-6), IL-1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), IL-4, IL-10, and tumor growth factor beta (TGF-ß) contents, while Western blot was applicated to measure inducible nitric oxide synthase (iNOS), arginase I (Arg-1) expression. Meanwhile, pyruvate kinase M2 (PKM2), hypoxia-inducible factor-1 alpha (HIF-1α) and its target genes glucose transporter type 1 (GLUT1), lactate dehydrogenase A (LDHA), and 3-phosphoinositide-dependent kinase 1 (PDK1), as well as IL-6, IL-1ß, TNF-α, IL-4, IL-10, and TGF-ß were evaluated by the quantitative reverse transcription-polymerase chain reaction. BHD treatment significantly reduced body weight and arteriosclerosis plaque area and blood lipid levels including total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Meanwhile, BHD demonstrated a significant suppression of M1 polarization, by decreased secretion of iNOS and pro-inflammatory factors (IL-6, IL-1ß, and TNF-α) in ApoE-/- mice. The present study also revealed that BHD promotes the activation of M2 polarization, characterized by the expression of Arg-1 and anti-inflammatory factors (IL-4 and IL-10). In addition, PKM2/HIF-1α signaling was improved by M1/M2 macrophages polarization induced by BHD. The downstream target genes (GLUT1, LDHA, and PDK1) expression was significantly increased in high fat feeding ApoE-/- mice, and those of which were recused by BHD and Atorvastatin. These results suggested that M1/M2 macrophages polarization produce the inflammatory response against AS progress after BHD exposure.


Subject(s)
Atherosclerosis , Drugs, Chinese Herbal , Macrophages , Animals , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Mice , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Atherosclerosis/metabolism , Macrophages/drug effects , Macrophages/metabolism , Male , Apolipoproteins E/genetics , Apolipoproteins E/deficiency , Disease Models, Animal , Mice, Knockout, ApoE , Mice, Knockout , Mice, Inbred C57BL , Cytokines/metabolism
6.
Article in English | MEDLINE | ID: mdl-38780293

ABSTRACT

ABSTRACT: The traditional Chinese herbal prescription Buyang Huanwu decoction (BHD), effectively treats atherosclerosis. However, the mechanism of BHD in atherosclerosis remains unclear. We aimed to determine whether BHD could alleviate atherosclerosis by altering the microbiome-associated metabolic changes in atherosclerotic mice. An atherosclerotic model was established in apolipoprotein E-deficient mice fed high-fat diet, and BHD was administered through gavage for 12 weeks at 8.4 g/kg/d and 16.8 g/kg/d. The atherosclerotic plaque size, composition, serum lipid profile, and inflammatory cytokines, were assessed. Mechanistically, metabolomic and microbiota profiles were analyzed by liquid chromatography-mass spectrometry and 16S rRNA gene sequencing, respectively. Furthermore, intestinal microbiota and atherosclerosis-related metabolic parameters were correlated using Spearman analysis. Atherosclerotic mice treated with BHD exhibited reduced plaque area, aortic lumen occlusion, and lipid accumulation in the aortic root. Nine perturbed serum metabolites were significantly restored along with the relative abundance of microbiota at the family and genus levels but not at the phylum level. Gut microbiome improvement was strongly negatively correlated with improved metabolite levels. BHD treatment effectively slows the progression of atherosclerosis by regulating altered intestinal microbiota and perturbed metabolites.


Subject(s)
Apolipoproteins E , Atherosclerosis , Diet, High-Fat , Drugs, Chinese Herbal , Gastrointestinal Microbiome , Animals , Gastrointestinal Microbiome/drug effects , Drugs, Chinese Herbal/pharmacology , Atherosclerosis/drug therapy , Atherosclerosis/pathology , Atherosclerosis/metabolism , Diet, High-Fat/adverse effects , Mice , Male , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Apolipoproteins E/metabolism , Mice, Inbred C57BL , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/pathology , Mice, Knockout , Mice, Knockout, ApoE
7.
Nutrients ; 16(10)2024 May 16.
Article in English | MEDLINE | ID: mdl-38794740

ABSTRACT

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.


Subject(s)
Apolipoproteins E , Atherosclerosis , Bile Acids and Salts , Cholesterol , Diet, High-Fat , Gastrointestinal Microbiome , Liver , Animals , Atherosclerosis/prevention & control , Atherosclerosis/metabolism , Bile Acids and Salts/metabolism , Mice , Cholesterol/blood , Cholesterol/metabolism , Gastrointestinal Microbiome/drug effects , Apolipoproteins E/genetics , Diet, High-Fat/adverse effects , Male , Liver/metabolism , Liver/drug effects , Mice, Inbred C57BL , Mice, Knockout , Disease Models, Animal , Lipid Metabolism/drug effects , Dietary Supplements , Feces/chemistry , Feces/microbiology , Mice, Knockout, ApoE , Receptors, Cytoplasmic and Nuclear/metabolism
8.
BMC Cardiovasc Disord ; 24(1): 275, 2024 May 28.
Article in English | MEDLINE | ID: mdl-38807081

ABSTRACT

BACKGROUND: Autophagy, as a regulator of cell survival, plays an important role in atherosclerosis (AS). Sperm associated antigen 5 (SPAG5) is closely associated with the classical autophagy pathway, PI3K/Akt/mTOR signaling pathway. This work attempted to investigate whether SPAG5 can affect AS development by regulating autophagy. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with oxidized-low density lipoprotein (ox-LDL) to induce cell damage. ApoE-/- mice were fed a Western diet to establish an AS mouse model. Haematoxylin and eosin (H&E) staining and Oil Red O staining evaluated the pathological changes and in lipid deposition in aortic tissues. CCK-8 and flow cytometry detected cell proliferation and apoptosis. Immunohistochemistry, Enzyme linked immunosorbent assay, qRT-PCR and western blotting assessed the levels of mRNA and proteins. RESULTS: Ox-LDL treatment elevated SPAG5 expression and the expression of autophagy-related proteins, LC3-I, LC3-II, Beclin-1, and p62, in HUVECs. GFP-LC3 dots were increased in ox-LDL-treated HUVECs and LPS-treated HUVECs. SPAG5 knockdown reversed both ox-LDL and LPS treatment-mediated inhibition of cell proliferation and promotion of apoptosis in HUVECs. SPAG5 silencing further elevated autophagy and repressed the expression of PI3K, p-Akt/Akt, and p-mTOR/mTOR in ox-LDL-treated HUVECs. 3-MA (autophagy inhibitor) treatment reversed SPAG5 silencing-mediated increase of cell proliferation and decrease of apoptosis in ox-LDL-treated HUVECs. In vivo, SPAG5 knockdown reduced atherosclerotic plaques in AS mice through activating autophagy and inhibiting PI3K/Akt/mTOR signaling pathway. CONCLUSION: This work demonstrated that SPAG5 knockdown alleviated AS development through activating autophagy. Thus, SPAG5 may be a potential target for AS therapy.


Subject(s)
Apoptosis , Atherosclerosis , Autophagy , Cell Proliferation , Disease Models, Animal , Human Umbilical Vein Endothelial Cells , Mice, Knockout, ApoE , Plaque, Atherosclerotic , Proto-Oncogene Proteins c-akt , Signal Transduction , TOR Serine-Threonine Kinases , Animals , Autophagy/drug effects , Human Umbilical Vein Endothelial Cells/metabolism , Human Umbilical Vein Endothelial Cells/pathology , Humans , Atherosclerosis/pathology , Atherosclerosis/metabolism , Atherosclerosis/genetics , Atherosclerosis/prevention & control , TOR Serine-Threonine Kinases/metabolism , Apoptosis/drug effects , Proto-Oncogene Proteins c-akt/metabolism , Cell Proliferation/drug effects , Aortic Diseases/pathology , Aortic Diseases/genetics , Aortic Diseases/prevention & control , Aortic Diseases/metabolism , Mice, Inbred C57BL , Lipoproteins, LDL/metabolism , Male , Cells, Cultured , Autophagy-Related Proteins/metabolism , Autophagy-Related Proteins/genetics , Aorta/pathology , Aorta/metabolism , Phosphatidylinositol 3-Kinase/metabolism , Cell Cycle Proteins/metabolism , Cell Cycle Proteins/genetics , Mice , Apolipoproteins E
9.
Front Immunol ; 15: 1327051, 2024.
Article in English | MEDLINE | ID: mdl-38807599

ABSTRACT

Introduction: The CC chemokine ligand 18 (CCL18) is a chemokine highly expressed in chronic inflammation in humans. Recent observations of elevated CCL18 plasma levels in patients with acute cardiovascular syndromes prompted an investigation into the role of CCL18 in the pathogenesis of human and mouse atherosclerosis. Methods and results: CCL18 was profoundly upregulated in ruptured human atherosclerotic plaque, particularly within macrophages. Repeated administration of CCL18 in Western-type diet-fed ApoE -/- mice or PCSK9mut-overexpressing wild type (WT) mice led to increased plaque burden, enriched in CD3+ T cells. In subsequent experimental and molecular modeling studies, we identified CCR6 as a functional receptor mediating CCL18 chemotaxis, intracellular Ca2+ flux, and downstream signaling in human Jurkat and mouse T cells. CCL18 failed to induce these effects in vitro in murine spleen T cells with CCR6 deficiency. The ability of CCR6 to act as CCL18 receptor was confirmed in vivo in an inflammation model, where subcutaneous CCL18 injection induced profound focal skin inflammation in WT but not in CCR6-/- mice. This inflammation featured edema and marked infiltration of various leukocyte subsets, including T cells with a Th17 signature, supporting CCR6's role as a Th17 chemotactic receptor. Notably, focal overexpression of CCL18 in plaques was associated with an increased presence of CCR6+ (T) cells. Discussion: Our studies are the first to identify the CCL18/CCR6 axis as a regulator of immune responses in advanced murine and human atherosclerosis.


Subject(s)
Atherosclerosis , Chemokines, CC , Receptors, CCR6 , Animals , Humans , Atherosclerosis/immunology , Atherosclerosis/metabolism , Mice , Receptors, CCR6/metabolism , Receptors, CCR6/genetics , Chemokines, CC/metabolism , Chemokines, CC/genetics , Disease Models, Animal , Mice, Inbred C57BL , Jurkat Cells , Plaque, Atherosclerotic/immunology , Mice, Knockout , Male , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Female , Mice, Knockout, ApoE
10.
Arterioscler Thromb Vasc Biol ; 44(6): 1365-1378, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38695170

ABSTRACT

BACKGROUND: Macrophages play a crucial role in atherosclerotic plaque formation, and the death of macrophages is a vital factor in determining the fate of atherosclerosis. GSDMD (gasdermin D)-mediated pyroptosis is a programmed cell death, characterized by membrane pore formation and inflammatory factor release. METHODS: ApoE-/- and Gsdmd-/- ApoE-/- mice, bone marrow transplantation, and AAV (adeno-associated virus serotype 9)-F4/80-shGSDMD (shRNA-GSDMD) were used to examine the effect of macrophage-derived GSDMD on atherosclerosis. Single-cell RNA sequencing was used to investigate the changing profile of different cellular components and the cellular localization of GSDMD during atherosclerosis. RESULTS: First, we found that GSDMD is activated in human and mouse atherosclerotic plaques and Gsdmd-/- attenuates the atherosclerotic lesion area in high-fat diet-fed ApoE-/- mice. We performed single-cell RNA sequencing of ApoE-/- and Gsdmd-/- ApoE-/- mouse aortas and showed that GSDMD is principally expressed in atherosclerotic macrophages. Using bone marrow transplantation and AAV-F4/80-shGSDMD, we identified the potential role of macrophage-derived GSDMD in aortic pyroptosis and atherosclerotic injuries in vivo. Mechanistically, GSDMD contributes to mitochondrial perforation and mitochondrial DNA leakage and subsequently activates the STING (stimulator of interferon gene)-IRF3 (interferon regulatory factor 3)/NF-κB (nuclear factor kappa B) axis. Meanwhile, GSDMD regulates the STING pathway activation and macrophage migration via cytokine secretion. Inhibition of GSDMD with GSDMD-specific inhibitor GI-Y1 (GSDMD inhibitor Y1) can effectively alleviate the progression of atherosclerosis. CONCLUSIONS: Our study has provided a novel macrophage-derived GSDMD mechanism in the promotion of atherosclerosis and demonstrated that GSDMD can be a potential therapeutic target for atherosclerosis.


Subject(s)
Atherosclerosis , Disease Models, Animal , Interferon Regulatory Factor-3 , Intracellular Signaling Peptides and Proteins , Macrophages , Membrane Proteins , Mice, Inbred C57BL , Mitochondria , NF-kappa B , Phosphate-Binding Proteins , Pyroptosis , Signal Transduction , Animals , Atherosclerosis/metabolism , Atherosclerosis/pathology , Atherosclerosis/genetics , Macrophages/metabolism , Membrane Proteins/metabolism , Membrane Proteins/genetics , Phosphate-Binding Proteins/metabolism , Phosphate-Binding Proteins/genetics , Interferon Regulatory Factor-3/metabolism , Interferon Regulatory Factor-3/genetics , Mice , NF-kappa B/metabolism , Mitochondria/metabolism , Mitochondria/pathology , Humans , Intracellular Signaling Peptides and Proteins/metabolism , Intracellular Signaling Peptides and Proteins/genetics , Male , Mice, Knockout, ApoE , Plaque, Atherosclerotic , Aortic Diseases/pathology , Aortic Diseases/metabolism , Aortic Diseases/genetics , Aortic Diseases/prevention & control , Gasdermins
11.
Pharmacology ; 109(3): 169-179, 2024.
Article in English | MEDLINE | ID: mdl-38583431

ABSTRACT

INTRODUCTION: Fisetin has been demonstrated to inhibit the occurrence of atherosclerosis; however, the mechanism of fisetin suppressing atherosclerosis remains elusive. METHODS: The function of fisetin in the inhibition of atherosclerosis was evaluated by hematoxylin and eosin and Oil Red O staining in ApoE-/- mice. Molecular biomarkers of atherosclerosis progression were detected by Western blot and qPCR. Moreover, the inhibition of atherosclerosis on oxidative stress and ferroptosis was evaluated by immunofluorescence staining, qPCR, and Western blot assays. RESULTS: The obtained results showed that serum lipid was attenuated and consequentially the formation of atherosclerosis was also suppressed by fisetin in ApoE-/- mice. Exploration of the mechanism revealed that molecular biomarkers of atherosclerosis were decreased under fisetin treatment. The level of reactive oxygen species and malondialdehyde declined, while the activity of superoxide dismutases and glutathione peroxidase was increased under the fisetin treatment. Additionally, the suppressor of ferroptosis, glutathione peroxidase 4 proteins, was elevated. The ferritin was decreased in the aortic tissues treated with fisetin. CONCLUSIONS: In summary, fisetin attenuated the formation of atherosclerosis through the inhibition of oxidative stress and ferroptosis in the aortic tissues of ApoE-/- mice.


Subject(s)
Apolipoproteins E , Atherosclerosis , Ferroptosis , Flavonols , Oxidative Stress , Animals , Flavonols/pharmacology , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Atherosclerosis/drug therapy , Oxidative Stress/drug effects , Ferroptosis/drug effects , Mice , Male , Apolipoproteins E/genetics , Mice, Knockout , Reactive Oxygen Species/metabolism , Mice, Inbred C57BL , Flavonoids/pharmacology , Mice, Knockout, ApoE , Aorta/drug effects , Aorta/metabolism , Aorta/pathology , Disease Models, Animal , Glutathione Peroxidase/metabolism
12.
J Ethnopharmacol ; 330: 118150, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-38631487

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: JiaWei DaChaiHu is composed of Bupleurum chinense, Scutellaria baicalensis, Pinellia ternata, Paeonia lactiflora, Zingiber officinaleRoscoe, Poncirus tuifoliata, Rheum palmatum L., Curcumae Radix, Herba Lysimachiae, Ziziphus. JiaWei DaChaiHu is one of the most common traditional Chinese medicines for the treatment of depression. AIM OF THE STUDY: The chronic unpredictable mild stress (CUMS) has been shown to promote atherosclerosis (AS). Dachaihu has been widely used in traditional Chinese medicine and has been known to exert distinct pharmacological effects. This investigation aims to examine the therapeutic effect of Jiawei Dachaihu extract on AS animal models with CUMS. METHODS: AS-CUMS mice model was established by Apoe-/- mice. Mice were treated with Jiawei Dachaihu. Serum total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL-C), high-density lipoprotein (HDL-C) levels were measured using ELISA kits. Aortic tissue pathologic changes detected by oil red O staining. Mice behavioral changes detected by sucrose preference test and sucrose preference test. The relative mRNA expression levels of CRH, ND1, and TFAM were determined by qRT-PCR. 5-HT1A, BDNF, LON, TFAM, PGC-1α, and SIRT1 protein expression determined by western blotting. ATP content detected by ATP kits. RESULTS: The treatment with Jiawei Dachaihu extract alleviated the veins plaque and reduced stress signs in vitro and in vivo. It increased the ATP and HDL-C levels while decreased the TC, TG, LDL-C levels. Jiawei Dachaihu extract treatment upregulated Lon, SIRT1, TFAM, PGC-1α, BDNF, and 5-HT1A protein expression and regained mitochondrial function. CONCLUSION: Jiawei Dachaihu extract could alleviate AS and reduce CUMS by upregulating the SIRT1/PGC-1α signaling and promoted its crosstalk with Lon protein to maintain mitochondrial stability.


Subject(s)
Atherosclerosis , Drugs, Chinese Herbal , Mitochondria , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Signal Transduction , Sirtuin 1 , Stress, Psychological , Animals , Atherosclerosis/drug therapy , Sirtuin 1/metabolism , Sirtuin 1/genetics , Drugs, Chinese Herbal/pharmacology , Drugs, Chinese Herbal/therapeutic use , Male , Signal Transduction/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Mice , Stress, Psychological/drug therapy , Mitochondria/drug effects , Mitochondria/metabolism , Mice, Inbred C57BL , Disease Models, Animal , Transcription Factors/metabolism , Transcription Factors/genetics , DNA-Binding Proteins/metabolism , DNA-Binding Proteins/genetics , Mice, Knockout, ApoE
13.
J Ethnopharmacol ; 330: 118209, 2024 Aug 10.
Article in English | MEDLINE | ID: mdl-38663779

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Dan-shen Yin (DSY), a traditional prescription, has been demonstrated to be effective in decreasing hyperlipidemia and preventing atherosclerosis (AS), but its mechanism remains unknown. We hypothesized that DSY activates farnesoid X receptor (FXR) to promote bile acid metabolism and excretion, thereby alleviating AS. AIM OF THE STUDY: This study was designed to explore whether DSY reduces liver lipid accumulation and prevents AS by activating FXR and increasing cholesterol metabolism and bile acid excretion. MATERIALS AND METHODS: The comprehensive chemical characterization of DSY was analyzed by UHPLC-MS/MS. The AS models of ApoE-/- mice and SD rats was established by high-fat diet and high-fat diet combined with intraperitoneal injection of vitamin D3, respectively. The aortic plaque and pathological changes were used to evaluate AS. Lipid levels, H&E staining and oil red O staining were used to evaluate liver lipid accumulation. The cholesterol metabolism and bile acid excretion were evaluated by enzyme-linked immunosorbent assay, UPLC-QQQ/MS. In vitro, the lipid and FXR/bile salt export pump (BSEP) levels were evaluated by oil red O staining, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting. RESULTS: A total of 36 ingredients in DSY were identified by UPLC-MS/MS analysis. In vivo, high-dose DSY significantly inhibited aortic intimal thickening, improved arrangement disorder, tortuosity, and rupture of elastic fibers, decreased lipid levels, and reduced the number of fat vacuoles and lipid droplets in liver tissue in SD rats and ApoE-/- mice. Further studies found that high-dose DSY significantly reduced liver lipid and total bile acids levels, increased liver ursodeoxycholic acid (UDCA) and other non-conjugated bile acids levels, increased fecal total cholesterol (TC) levels, and augmented FXR, BSEP, cholesterol 7-alpha hydroxylase (CYP7A1), ATP binding cassette subfamily G5/G8 (ABCG5/8) expression levels, while decreasing ASBT expression levels. In vitro studies showed that DSY significantly reduced TC and TG levels, as well as lipid droplets, while also increasing the expression of ABCG5/8, FXR, and BSEP in both HepG2 and Nr1h4 knockdown HepG2 cells. CONCLUSION: This study demonstrated that DSY promotes bile acid metabolism and excretion to prevent AS by activating FXR. For the prevent of AS and drug discovery provided experimental basis.


Subject(s)
Atherosclerosis , Bile Acids and Salts , Drugs, Chinese Herbal , Signal Transduction , Animals , Humans , Male , Mice , Rats , Atherosclerosis/prevention & control , Atherosclerosis/metabolism , Atherosclerosis/drug therapy , ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism , Bile Acids and Salts/metabolism , Diet, High-Fat/adverse effects , Drugs, Chinese Herbal/pharmacology , Lipid Metabolism/drug effects , Liver/drug effects , Liver/metabolism , Liver/pathology , Mice, Inbred C57BL , Mice, Knockout, ApoE , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/metabolism , Signal Transduction/drug effects
14.
Nutrients ; 16(8)2024 Apr 17.
Article in English | MEDLINE | ID: mdl-38674885

ABSTRACT

The cellular and molecular mechanisms of atherosclerosis are still unclear. Type 2 innate lymphocytes (ILC2) exhibit anti-inflammatory properties and protect against atherosclerosis. This study aimed to elucidate the pathogenesis of atherosclerosis development using atherosclerosis model mice (ApoE KO mice) and mice deficient in IL-33 receptor ST2 (ApoEST2 DKO mice). Sixteen-week-old male ApoE KO and ApoEST2 DKO mice were subjected to an 8-week regimen of a high-fat, high-sucrose diet. Atherosclerotic foci were assessed histologically at the aortic valve ring. Chronic inflammation was assessed using flow cytometry and real-time polymerase chain reaction. In addition, saturated fatty acids (palmitic acid) and IL-33 were administered to human aortic endothelial cells (HAECs) to assess fatty acid metabolism. ApoEST2 DKO mice with attenuated ILC2 had significantly worse atherosclerosis than ApoE KO mice. The levels of saturated fatty acids, including palmitic acid, were significantly elevated in the arteries and serum of ApoEST2 DKO mice. Furthermore, on treating HAECs with saturated fatty acids with or without IL-33, the Oil Red O staining area significantly decreased in the IL-33-treated group compared to that in the non-treated group. IL-33 potentially prevented the accumulation of saturated fatty acids within atherosclerotic foci.


Subject(s)
Atherosclerosis , Fatty Acids , Interleukin-33 , Mice, Knockout , Animals , Interleukin-33/metabolism , Interleukin-33/genetics , Atherosclerosis/metabolism , Male , Mice , Fatty Acids/metabolism , Humans , Disease Models, Animal , Palmitic Acid/pharmacology , Apolipoproteins E/genetics , Apolipoproteins E/deficiency , Diet, High-Fat , Interleukin-1 Receptor-Like 1 Protein/metabolism , Interleukin-1 Receptor-Like 1 Protein/genetics , Endothelial Cells/metabolism , Mice, Knockout, ApoE , Lymphocytes/metabolism , Mice, Inbred C57BL , Aorta/metabolism , Aorta/pathology , Immunity, Innate
15.
Atherosclerosis ; 393: 117554, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38663275

ABSTRACT

BACKGROUND AND AIMS: Long noncoding RNAs (lncRNAs) play important roles in the progression of atherosclerosis. In this study, we identified an uncharacterized lncRNA, Liver Expressions by PSRC1 Induced Specifically (LEPIS). This study aimed to clarify the mechanism though which LEPIS affects atherosclerosis (AS). METHODS: The expression of LEPIS and its potential target, tropomodulin 4 (TMOD4), was increased in the livers of ApoE-/- mice fed a high-fat diet (HFD). An ApoE-/- mouse model in which LEPIS or TMOD4 was overexpressed in the liver was established. The plaque load in the aorta was assessed, plasma was collected to measure blood lipid levels, and the liver was collected to study cholesterol metabolism. RESULTS: We found that both LEPIS and TMOD4 increased the AS burden and reduced hepatic cholesterol levels. A further study revealed that LEPIS and TMOD4 affected the expression of genes related to hepatic cholesterol homeostasis, including proprotein convertase subtilisin/kexin type 9 (PCSK9) and low-density lipoprotein receptor (LDLR), which are closely related to hypercholesterolemia. Mechanistically, human antigen R (HuR), an RNA-binding protein (RBP), was shown to be critical for the regulation of TMOD4 by LEPIS. Furthermore, we found that verexpression of LEPIS promoted the shuttling of HuR from the nucleus to the cytoplasm, enhanced the stability of TMOD4 mRNA, and in turn promoted the expression of TMOD4. In addition, TMOD4 was found to affect intracellular cholesterol levels through PCSK9. CONCLUSIONS: These results suggest that the LEPIS-HuR-TMOD4 axis is a potential intervention target for dysregulated hepatic cholesterol homeostasis and AS and may provide the basis for further reductions in the circulating LDL-C concentration and arterial plaque burden.


Subject(s)
Atherosclerosis , Cholesterol , Disease Models, Animal , Homeostasis , Liver , Mice, Knockout, ApoE , Animals , Humans , Male , Mice , Aortic Diseases/metabolism , Aortic Diseases/genetics , Aortic Diseases/pathology , Atherosclerosis/metabolism , Atherosclerosis/genetics , Atherosclerosis/pathology , Cholesterol/metabolism , Cholesterol/blood , Diet, High-Fat , ELAV-Like Protein 1/metabolism , ELAV-Like Protein 1/genetics , Liver/metabolism , Mice, Inbred C57BL , Plaque, Atherosclerotic , Proprotein Convertase 9/metabolism , Proprotein Convertase 9/genetics , Receptors, LDL/genetics , Receptors, LDL/metabolism , RNA, Long Noncoding/genetics , RNA, Long Noncoding/metabolism
16.
J Ethnopharmacol ; 332: 118245, 2024 Oct 05.
Article in English | MEDLINE | ID: mdl-38679399

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: The 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. AIM: This 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 METHODS: AS 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. RESULTS: After 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). CONCLUSION: Xuefu 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.


Subject(s)
Atherosclerosis , Diet, High-Fat , Drugs, Chinese Herbal , Signal Transduction , Animals , Drugs, Chinese Herbal/pharmacology , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Mice , Signal Transduction/drug effects , Male , Diet, High-Fat/adverse effects , Chemokines/metabolism , Chemokines/genetics , Gene Expression Profiling/methods , Mice, Knockout, ApoE , Mice, Inbred C57BL , Plaque, Atherosclerotic/drug therapy , Disease Models, Animal , Transcriptome/drug effects , Macrophages/drug effects , Macrophages/metabolism , Apolipoproteins E/genetics , Aorta/drug effects , Aorta/pathology
17.
PLoS One ; 19(4): e0302387, 2024.
Article in English | MEDLINE | ID: mdl-38635560

ABSTRACT

The aim of this study was to elucidate the specific mechanism through which 7-difluoromethoxy-5,4'-dimethoxygenistein (DFMG) inhibits angiogenesis in atherosclerosis (AS) plaques, given its previously observed but poorly understood inhibitory effects. In vitro, a model using Human Umbilical Vein Endothelial (HUVEC-12) cells simulated the initial lesion in the atherosclerotic pathological process, specifically oxidative stress injury, by exposing cells to 30 µmol/L LPC. Additionally, an AS mouse model was developed in ApoE knockout mice through a 16-week period of high-fat feeding. DFMG demonstrated a reduction in tubule quantities in the tube formation assay and neovascularization induced by oxidative stress-damaged endothelial cells in the chicken embryo chorioallantoic membrane assay. Furthermore, DFMG decreased lipid levels in the blood of ApoE knockout mice with AS, along with a decrease in atherosclerotic plaques and neovascularizations in the aortic arch and descending aorta of AS animal models. DFMG treatment upregulated microRNA140 (miR-140) expression and suppressed VEGF secretion in HUVEC-12 cells. These effects were counteracted by Toll-like receptor 4 (TLR4) overexpression in HUVEC-12 cells subjected to oxidative injury or in a mouse model of AS. Dual-luciferase reporter assays demonstrated that miR-140 directly targeted TLR4. Immunohistochemical assay findings indicated a significant inverse relationship between miR-140 expression and TLR4 expression in ApoE knockout mice subjected to a high-fat diet. The study observed a close association between DFMG inhibitory effects on angiogenesis and plaque stability in AS, and the inhibition of the TLR4/NF-κB/VEGF signaling pathway, negatively regulated by miR-140.


Subject(s)
MicroRNAs , Plaque, Atherosclerotic , Chick Embryo , Humans , Animals , Mice , Plaque, Atherosclerotic/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Vascular Endothelial Growth Factor A/metabolism , Mice, Knockout, ApoE , Angiogenesis , NF-kappa B/metabolism , Human Umbilical Vein Endothelial Cells/metabolism , MicroRNAs/metabolism , Mice, Knockout
18.
J Transl Med ; 22(1): 352, 2024 Apr 15.
Article in English | MEDLINE | ID: mdl-38622667

ABSTRACT

BACKGROUND: Quinic acid (QA) and its derivatives have good lipid-lowering and hepatoprotective functions, but their role in atherosclerosis remains unknown. This study attempted to investigate the mechanism of QA on atherogenesis in Apoe-/- mice induced by HFD. METHODS: HE staining and oil red O staining were used to observe the pathology. The PCSK9, Mac-3 and SM22a expressions were detected by IHC. Cholesterol, HMGB1, TIMP-1 and CXCL13 levels were measured by biochemical and ELISA. Lipid metabolism and the HMGB1-SREBP2-SR-BI pathway were detected by PCR and WB. 16 S and metabolomics were used to detect gut microbiota and serum metabolites. RESULTS: QA or low-frequency ABX inhibited weight gain and aortic tissue atherogenesis in HFD-induced Apoe-/- mice. QA inhibited the increase of cholesterol, TMA, TMAO, CXCL13, TIMP-1 and HMGB1 levels in peripheral blood of Apoe-/- mice induced by HFD. Meanwhile, QA or low-frequency ABX treatment inhibited the expression of CAV-1, ABCA1, Mac-3 and SM22α, and promoted the expression of SREBP-1 and LXR in the vascular tissues of HFD-induced Apoe-/- mice. QA reduced Streptococcus_danieliae abundance, and promoted Lactobacillus_intestinalis and Ileibacterium_valens abundance in HFD-induced Apoe-/- mice. QA altered serum galactose metabolism, promoted SREBP-2 and LDLR, inhibited IDOL, FMO3 and PCSK9 expression in liver of HFD-induced Apoe-/- mice. The combined treatment of QA and low-frequency ABX regulated microbe-related Glycoursodeoxycholic acid and GLYCOCHENODEOXYCHOLATE metabolism in HFD-induced Apoe-/- mice. QA inhibited TMAO or LDL-induced HCAECs damage and HMGB1/SREBP2 axis dysfunction, which was reversed by HMGB1 overexpression. CONCLUSIONS: QA regulated the gut-liver lipid metabolism and chronic vascular inflammation of TMA/TMAO through gut microbiota to inhibit the atherogenesis in Apoe-/- mice, and the mechanism may be related to the HMGB1/SREBP2 pathway.


Subject(s)
Atherosclerosis , Gastrointestinal Microbiome , HMGB1 Protein , Methylamines , Mice , Animals , Proprotein Convertase 9 , HMGB1 Protein/metabolism , Quinic Acid , Sterol Regulatory Element Binding Protein 1/metabolism , Tissue Inhibitor of Metalloproteinase-1/metabolism , Lipid Metabolism , Mice, Knockout, ApoE , Atherosclerosis/pathology , Inflammation , Cholesterol , Apolipoproteins E/metabolism , Mice, Inbred C57BL
19.
Phytomedicine ; 128: 155526, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38564921

ABSTRACT

BACKGROUND: Atherosclerosis (AS) is an important cause of cardiovascular disease, posing a substantial health risk. Recognized as a chronic inflammatory disorder, AS hinges on the pivotal involvement of macrophages in arterial inflammation, participating in its formation and progression. Sangzhi alkaloid (SZ-A) is a novel natural alkaloid extracted from the mulberry branches, has extensive pharmacological effects and stable pharmacokinetic characteristics. However, the effects and mechanisms of SZ-A on AS remain unclear. PURPOSE: To explore the effect and underlying mechanisms of SZ-A on inflammation mediated by macrophages and its role in AS development. METHODS: Atherosclerosis was induced in vivo in apolipoprotein E-deficient mice through a high-fat and high-choline diet. We utilized macrophages and vascular endothelial cells to investigate the effects of SZ-A on macrophage polarization and its anti-inflammatory properties on endothelial cells in vitro. The transcriptomic analyses were used to investigate the major molecule that mediates cell-cell interactions and the antiatherogenic mechanisms of SZ-A based on AS, subsequently validated in vivo and in vitro. RESULTS: SZ-A demonstrated a significant inhibition in vascular inflammation and alleviation of AS severity by mitigating macrophage infiltration and modulating M1/M2 macrophage polarization in vitro and in vivo. Moreover, SZ-A effectively reduced the release of the proinflammatory mediator C-X-C motif chemokine ligand (CXCL)-10, predominantly secreted by M1 macrophages. This reduction in CXCL-10 contributed to improved endothelial cell function, reduced recruitment of additional macrophages, and inhibited the inflammatory amplification effect. This ultimately led to the suppression of atherogenesis. CONCLUSION: SZ-A exhibited potent anti-inflammatory effects by inhibiting macrophage-mediated inflammation, providing a new therapeutic avenue against AS. This is the first study demonstrating the efficacy of SZ-A in alleviating AS severity and offers novel insights into its anti-inflammatory mechanism.


Subject(s)
Alkaloids , Atherosclerosis , Macrophages , Morus , Animals , Atherosclerosis/drug therapy , Macrophages/drug effects , Mice , Alkaloids/pharmacology , Morus/chemistry , Male , Mice, Inbred C57BL , Anti-Inflammatory Agents/pharmacology , Diet, High-Fat , Humans , RAW 264.7 Cells , Mice, Knockout, ApoE , Endothelial Cells/drug effects , Apolipoproteins E
SELECTION OF CITATIONS
SEARCH DETAIL
...