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1.
J Ethnopharmacol ; 301: 115787, 2023 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-36206868

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Atherosclerosis (AS) is a common pathogenesis of cardiovascular diseases. Qingre Huoxue Decoction (QRHX) is an herbal formula used for the prevention and treatment of AS. However, the potential mechanism of QRHX is not clear. AIM OF THE STUDY: In our study, RNA sequencing combined with preclinical models were used to analyse the effect and mechanism of QRHX for the treatment of AS. MATERIALS AND METHODS: For in vivo studies, ApoE-/- mice were fed with a high-fat diet to induce AS. We measured weight, blood lipid, inflammatory cytokines, lipid deposition, plaque, and the M1/M2 macrophage. For in vitro studies, RAW264.7 were induced by lipopolysaccharides and treated with different concentrations of QRHX. We focusd on the relationship between QRHX, the NF-κB pathway, and macrophage polarisation, and performed simultaneous RNA sequencing both in vivo and in vitro. RESULTS: In vivo, QRHX decreased weight, improved blood lipid, relieved the degree of lipid deposition, reduced plaque area, decreased the levels of inflammatory cytokines (MCP-1, NLRP3, and TNFα), down-regulated the expression of iNOS, and up-regulated the expression of Arg-1. In vitro, QRHX down-regulated M1 markers, iNOS and CCR7, with lower concentrations of IL-1ß; furthermore, QRHX up-regulated M2 markers, Arg-1, CD163, Ym-1, and Fizz-1, with higher concentrations of IL-4 and IL-10. RNA sequencing of both samples in vivo and in vitro suggested that NF-κB was the target pathway of QRHX to regulate macrophage polarisation; this result was validated at the gene and protein levels. CONCLUSIONS: QRHX induced M2 polarisation, reduced an inflammatory response, and played a role in stabilising plaque by mediating the NF-κB signalling pathway.


Assuntos
Aterosclerose , Placa Aterosclerótica , Camundongos , Animais , NF-kappa B/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Macrófagos , Lipopolissacarídeos/farmacologia , Citocinas/metabolismo , Placa Aterosclerótica/patologia
2.
Curr Top Membr ; 90: 123-139, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36368871

RESUMO

Vascular smooth muscle cells express several isoforms of a number of classes of K+ channels. Potassium channels play critical roles in the regulation of vascular smooth muscle contraction as well as vascular smooth muscle cell proliferation or phenotypic modulation. There is ample evidence that it is Ca2+ that enables these two seemingly disparate functions to be tightly coupled both in healthy and disease processes. Because of the central position that potassium channels have in vasocontraction, vasorelaxation, membrane potential, and smooth muscle cell proliferation, these channels continue to possess the potential to serve as novel therapeutic targets in cardiovascular disease. While there are questions that remain regarding the complete interactions between K+ channels, vascular regulation, smooth muscle cell proliferation, and phenotypic modulation in physiological and pathophysiological conditions, a broad understanding of the contributions of each class of K+ channel to contractile and proliferative states of the vasculature has been reached. This brief review will discuss the current understanding of the role of K+ channels in vascular smooth muscle cells in health and disease using the porcine vascular smooth muscle cell model with particular attention to new scientific discoveries contributed by the authors regarding the effect of endurance exercise on the function of the K+ channels.


Assuntos
Aterosclerose , Músculo Liso Vascular , Suínos , Animais , Músculo Liso Vascular/fisiologia , Canais de Potássio/metabolismo , Potenciais da Membrana , Contração Muscular , Aterosclerose/metabolismo
3.
Biomed Khim ; 68(5): 361-366, 2022 Nov.
Artigo em Russo | MEDLINE | ID: mdl-36373882

RESUMO

It was shown, that genotoxic stress can trigger endothelial disfunction and atherosclerosis, but the molecular genetic mechanisms of this process are poorly investigated. At the same time, inflammation also plays the important role in atherogenesis. This study aimed access of inflammatory marker expression in the endothelial cells exposed to alkylating mutagen mitomycin C (MMC). Primary human coronary (HCAEC) and internal thoracic artery endothelial cells (HITAEC) exposed to 500 ng/ml MMC (experimental group) and 0.9% NaCl (control) were used in this research. A gene expression profile was evaluated by quantitative reverse transcription PCR after 6 h exposure of endothelial cells to MMC (or 0.9% NaCl) followed by subsequent 24 h incubation in the mutagen-free cell growth media. The cytokine profile of endotheliocytes was studied by dot blotting. We found that MIF, IL-8, MCP-1, IP-10 and PDGFB were upregulated both in HCAEC and HITAEC, while MIP-1ß release remained unchanged. TIMP-2 was upregulated in HCAEC but not in HITAEC. sTNF RI was expressed only in HCAEC. According to gene expression analysis, HCAEC exposed to MMC are characterized by the increased mRNA level of IL-8, MCP-1 and IP-10; decreased expression of TIMP-2 and no differences in the expression of MIF, MIP-1ß and PDGFB compared to the control. In HITAEC, increased mRNA level of IL-8 and IP-10; decreased expression of MIF and TIMP-2, no differences in the expression of MCP-1, MIP-1ß and PDGFB was shown. TNF-RI expression was not detected in both cell lines. Thus, genotoxic stress in endothelial cells induced by MMC leads to differential inflammatory response that can trigger endothelial dysfunction.


Assuntos
Aterosclerose , Células Endoteliais , Humanos , Células Endoteliais/metabolismo , Inibidor Tecidual de Metaloproteinase-2/genética , Inibidor Tecidual de Metaloproteinase-2/metabolismo , Interleucina-8/genética , Interleucina-8/metabolismo , Vasos Coronários/metabolismo , Quimiocina CCL4/genética , Quimiocina CCL4/metabolismo , Proteínas Proto-Oncogênicas c-sis/genética , Proteínas Proto-Oncogênicas c-sis/metabolismo , Solução Salina/metabolismo , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , RNA Mensageiro/genética , Aterosclerose/metabolismo , Dano ao DNA , Células Cultivadas
4.
Nutrients ; 14(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36364780

RESUMO

Atherosclerosis is a chronic inflammatory vascular disease in which endothelial cells play an important role in maintaining vascular homeostasis. Endotheliitis caused by endothelial dysfunction (ED) is the key cause for the development of cardiovascular and cerebrovascular diseases as well as other vascular system diseases. Resveratrol (RES), a multi-functional polyphenol present in edible plants and fruits, prevents cardiovascular disease by regulating a variety of athero-relevant signaling pathways. By transcriptome profiling of RES-treated human umbilical vein endothelial cells (HUVECs) and in-depth bioinformatic analysis, we observed that differentially expressed genes (DEGs) were enriched in KEGG pathways of fluid shear stress and atherosclerosis, suggesting that the RES may serve as a good template for a shear stress mimetic drug that hold promise in combating atherosclerosis. A heat map and multiple datasets superimposed screening revealed that RES significantly down-regulated phosphatase and actin modulator 1 (PHACTR1), a pivotal coronary artery disease risk gene associated with endothelial inflammation and polyvascular diseases. We further demonstrate that RES down-regulated the gene and protein expression of PHACTR1 and inhibited TNF-α-induced adhesion of THP-1 monocytes to activated endothelial cells via suppressing the expression of PHACTR1. Taken together, our study reveals that PHACTR1 represents a new molecular target for RES to maintain endothelial cell homeostasis and prevent atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Humanos , Resveratrol/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Homeostase
5.
Biomolecules ; 12(11)2022 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-36358920

RESUMO

Cardiovascular disease is currently the leading cause of death worldwide. Atherosclerosis is an important pathological basis of cardiovascular disease, and its early diagnosis is of great significance. Urine bears no need nor mechanism to be stable, so it accumulates many small changes and is therefore a good source of biomarkers in the early stages of disease. In this study, ApoE-/- mice were fed a high-fat diet for 5 months. Urine samples from the experimental group and control group (C57BL/6 mice fed a normal diet) were collected at seven time points. Proteomic analysis was used for comparison within the experimental group and for comparison between the experimental group and the control group. The results of the comparison within the experimental group showed a significant difference in the urinary proteome before and after a one-week high-fat diet, and several of the differential proteins have been reported to be associated with atherosclerosis and/or as biomarker candidates. The results of the comparison between the experimental group and the control group indicated that the biological processes enriched by the GO analysis of the differential proteins correspond to the progression of atherosclerosis. The differences in chemical modifications of urinary proteins have also been reported to be associated with the disease. This study demonstrates that urinary proteomics has the potential to sensitively monitor changes in the body and provides the possibility of identifying early biomarkers of atherosclerosis.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Camundongos , Animais , Proteoma , Dieta Hiperlipídica/efeitos adversos , Proteômica/métodos , Camundongos Endogâmicos C57BL , Doenças Cardiovasculares/complicações , Camundongos Knockout para ApoE , Camundongos Knockout , Apolipoproteínas E , Aterosclerose/metabolismo , Biomarcadores
6.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361795

RESUMO

Neuropeptide Y (NPY) is an abundantly expressed peptide capable of modulating innate and adaptive immune responses and regulating chemotaxis and cytokine secretion by macrophages. Abnormal regulation of NPY is involved in the development of atherosclerosis. The inflammatory infiltrate within atherosclerotic plaque is characterized by accumulation of macrophages, which are subject to reprogram their phenotypes in response to environmental signals. Macrophage number and phenotype influence plaque fate. Here, we investigated the effect of NPY on the changes in phenotype and functions of human macrophages, from the pro-inflammatory phenotype M1 to the reparative M2, indicative of atherosclerosis regression or stabilization. Human monocytes were differentiated in vitro into macrophages with M-CSF (M0) and polarized towards an M1 phenotype with IFN-γ plus LPS M(IFN-γ/LPS) or M2 with IL-10 (M IL-10) and further challenged with NPY (10-7-10-9 M) for 8-36 h. Cell phenotype and functions were analyzed by immunofluorescence and immunochemical analyses. NPY affected macrophage surface markers and secretome profile expression, thus shifting macrophages toward an M2-like phenotype. NPY also prevented the impairment of endocytosis triggered by the oxysterol 7-keto-cholesterol (7KC) and prevented 7KC-induced foam cell formation by reducing the lipid droplet accumulation in M0 macrophages. NPY-treated M0 macrophages enhanced the autophagosome formation by upregulating the cell content of the autophagy markers LC3-II and p62-SQSTM1, increased activation of the anti-oxidative transcription factor NRF2 (NF-E2-related factor 2), and subsequently induced its target gene HMOX1 that encodes heme oxygenase-1. Our findings indicate that NPY has a cytoprotective effect with respect to the progression of the inflammatory pathway, both enhancing p62/SQSTM1-dependent autophagy and the NRF2-antioxidant signaling pathway in macrophages. NPY signaling may have a crucial role in tissue homeostasis in host inflammatory responses through the regulation of macrophage balance and functions within atherosclerosis.


Assuntos
Aterosclerose , Interleucina-10 , Humanos , Interleucina-10/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Neuropeptídeo Y/metabolismo , Proteína Sequestossoma-1/metabolismo , Lipopolissacarídeos/farmacologia , Macrófagos/metabolismo , Ativação de Macrófagos , Autofagia , Aterosclerose/metabolismo
7.
Eur J Med Chem ; 244: 114866, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36368255

RESUMO

Lipids-lowering is considered as the most effective approach to decrease the risk of Atherosclerotic cardiovascular disease (ASCVD), of which atherosclerosis is the most common cause. Natural products containing a unique type of α-pyrone was reported to suppress atherosclerosis in which α-pyrone might be considered as an important pharmacore. In this study, an efficient one-pot intramolecular C-H activation strategy was applied to the synthesis of potentially bioactive α-pyrone derivatives. As the result, three different scaffolds were quickly and conveniently generated, including thiophenes, pyrrole and indole derivatives. Among of them, eight α-pyrone derivatives showed potential effects to promote the uptake of LDL in HepG2 cells. Active unique α-pyrones compounds exhibiting potent in vitro and in vivo lipids-lowering effects, and a novel mechanism associated with the regulation of LXR-IDOL-LDLR axis, the new pathway targeted pharmacologically to control plasma cholesterol levels, were disclosed firstly in this study.


Assuntos
Aterosclerose , Receptores de LDL , Humanos , Receptores de LDL/metabolismo , Receptores Nucleares Órfãos/metabolismo , Receptores X do Fígado/metabolismo , Pironas/metabolismo , Ubiquitina-Proteína Ligases/metabolismo , Fígado/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Lipídeos
8.
Nat Commun ; 13(1): 6647, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36333342

RESUMO

Endothelial nitric oxide synthase (eNOS) decreases following inflammatory stimulation. As a master regulator of endothelial homeostasis, maintaining optimal eNOS levels is important during cardiovascular events. However, little is known regarding the mechanism of eNOS protection. In this study, we demonstrate a regulatory role for endothelial expression of 2'-5' oligoadenylate synthetase-like 1 (OASL1) in maintaining eNOS mRNA stability during athero-prone conditions and consider its clinical implications. A lack of endothelial Oasl1 accelerated plaque progression, which was preceded by endothelial dysfunction, elevated vascular inflammation, and decreased NO bioavailability following impaired eNOS expression. Mechanistically, knockdown of PI3K/Akt signaling-dependent OASL expression increased Erk1/2 and NF-κB activation and decreased NOS3 (gene name for eNOS) mRNA expression through upregulation of the negative regulatory, miR-584, whereas a miR-584 inhibitor rescued the effects of OASL knockdown. These results suggest that OASL1/OASL regulates endothelial biology by protecting NOS3 mRNA and targeting miR-584 represents a rational therapeutic strategy for eNOS maintenance in vascular disease.


Assuntos
Aterosclerose , MicroRNAs , Humanos , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Ligases/metabolismo , Células Endoteliais/metabolismo , MicroRNAs/genética , Aterosclerose/genética , Aterosclerose/prevenção & controle , Aterosclerose/metabolismo , RNA Mensageiro/metabolismo , Estabilidade de RNA , Óxido Nítrico/metabolismo , Células Cultivadas
9.
Front Immunol ; 13: 1039241, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36389728

RESUMO

The endothelium is a single layer of epithelium covering the surface of the vascular system, and it represents a physical barrier between the blood and vessel wall that plays an important role in maintaining intravascular homeostasis. However, endothelial dysfunction or endothelial cell death can cause vascular barrier disruption, vasoconstriction and diastolic dysfunction, vascular smooth muscle cell proliferation and migration, inflammatory responses, and thrombosis, which are closely associated with the progression of several diseases, such as atherosclerosis, hypertension, coronary atherosclerotic heart disease, ischemic stroke, acute lung injury, acute kidney injury, diabetic retinopathy, and Alzheimer's disease. Oxidative stress caused by the overproduction of reactive oxygen species (ROS) is an important mechanism underlying endothelial cell death. Growing evidence suggests that ROS can trigger endothelial cell death in various ways, including pyroptosis, parthanatos, and ferroptosis. Therefore, this review will systematically illustrate the source of ROS in endothelial cells (ECs); reveal the molecular mechanism by which ROS trigger pyroptosis, parthanatos, and ferroptosis in ECs; and provide new ideas for the research and treatment of endothelial dysfunction-related diseases.


Assuntos
Aterosclerose , Ferroptose , Hipertensão , Parthanatos , Humanos , Células Endoteliais/metabolismo , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Endotélio Vascular/metabolismo , Aterosclerose/metabolismo
10.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-36362449

RESUMO

Phosphorylcholine (PC) is one of the main oxLDL epitopes playing a central role in atherosclerosis, due to its atherogenic and proinflammatory effects. PC can be cleared by natural IgM antibodies and low levels of these antibodies have been associated with human vein graft (VG) failure. Although PC antibodies are recognized for their anti-inflammatory properties, their effect on intraplaque angiogenesis (IPA) and intraplaque hemorrhage (IPH)-interdependent processes contributing to plaque rupture-are unknown. We hypothesized that new IgG phosphorylcholine antibodies (PC-mAb) could decrease vulnerable lesions in murine VGs.Therefore, hypercholesterolemic male ApoE3*Leiden mice received a (donor) caval vein interposition in the carotid artery and weekly IP injections of (5 mg/kg) PCmAb (n = 11) or vehicle (n = 12) until sacrifice at day 28. We found that PCmAb significantly decreased vein graft media (13%), intima lesion (25%), and increased lumen with 32% compared to controls. PCmAb increased collagen content (18%) and decreased macrophages presence (31%). PCmAb resulted in 23% decreased CD163+ macrophages content in vein grafts whereas CD163 expression was decreased in Hb:Hp macrophages. PCmAb significantly lowered neovessel density (34%), EC proliferation and migration with/out oxLDL stimulation. Moreover, PCmAb enhanced intraplaque angiogenic vessels maturation by increasing neovessel pericyte coverage in vivo (31%). Together, this resulted in a 62% decrease in IPH. PCmAb effectively inhibits murine atherosclerotic lesion formation in vein grafts by reducing IPA and IPH via decreased neovessel density and macrophages influx and increased neovessel maturation. PC-mAb therefore holds promise as a new therapeutic approach to prevent vein graft disease.


Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Camundongos , Masculino , Animais , Fosforilcolina/farmacologia , Placa Aterosclerótica/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/complicações , Aterosclerose/metabolismo , Hemorragia/metabolismo , Anticorpos Monoclonais
11.
Cell Commun Signal ; 20(1): 180, 2022 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-36411459

RESUMO

Vascular smooth muscle cells (VSMCs) are the most abundant cell in vessels. Earlier experiments have found that VSMCs possess high plasticity. Vascular injury stimulates VSMCs to switch into a dedifferentiated type, also known as synthetic VSMCs, with a high migration and proliferation capacity for repairing vascular injury. In recent years, largely owing to rapid technological advances in single-cell sequencing and cell-lineage tracing techniques, multiple VSMCs phenotypes have been uncovered in vascular aging, atherosclerosis (AS), aortic aneurysm (AA), etc. These VSMCs all down-regulate contractile proteins such as α-SMA and calponin1, and obtain specific markers and similar cellular functions of osteoblast, fibroblast, macrophage, and mesenchymal cells. This highly plastic phenotype transformation is regulated by a complex network consisting of circulating plasma substances, transcription factors, growth factors, inflammatory factors, non-coding RNAs, integrin family, and Notch pathway. This review focuses on phenotypic characteristics, molecular profile and the functional role of VSMCs phenotype landscape; the molecular mechanism regulating VSMCs phenotype switching; and the contribution of VSMCs phenotype switching to vascular aging, AS, and AA. Video Abstract.


Assuntos
Aterosclerose , Lesões do Sistema Vascular , Humanos , Músculo Liso Vascular/fisiologia , Lesões do Sistema Vascular/metabolismo , Proliferação de Células , Fenótipo , Aterosclerose/metabolismo
12.
Molecules ; 27(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36296612

RESUMO

Tripeptide LSW, initially identified as a potent ACE inhibitory peptide from soybean protein, was recently reported to exert a protective effect against angiotensin II-induced endothelial dysfunction via extracellular vesicles (EVs). However, the molecular mechanisms, especially in lipid accumulation-induced atherosclerosis, still remain unclear. The study aimed to investigate whether the protective effects of LSW against endothelial dysfunction on vascular endothelial cells (VECs) was via vascular smooth muscle cells (VSMCs)-derived miRNA-145 packaged in EVs. The miRNA-145 was concentrated in EVs from LSW-treated VSMCs (LEVs), internalized into the HVUECs, and targeted the programmed cell death protein 4 (PDCD4) expression of HUVECs. Oxidized low-density lipoprotein (oxLDL) was applied to induce endothelial dysfunction in HUVECs; oxLDL-induced endothelial dysfunction in HUVECs was attenuated by PDCD4 knockout or LEVs incubation. The results of this study suggested a novel function of LSW as a regulator on the functional EVs from vascular cells in the oxLDL-induced atherosclerotic model.


Assuntos
Aterosclerose , Vesículas Extracelulares , MicroRNAs , Humanos , Células Endoteliais , Músculo Liso Vascular/metabolismo , Angiotensina II/metabolismo , Proteínas de Soja/farmacologia , Miócitos de Músculo Liso/metabolismo , Lipoproteínas LDL/farmacologia , Lipoproteínas LDL/metabolismo , Vesículas Extracelulares/metabolismo , Aterosclerose/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Fenótipo , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas de Ligação a RNA/metabolismo
13.
Cardiovasc Ther ; 2022: 3328574, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36313479

RESUMO

Ischemic stroke, which occurs following blockage of the blood supply to the brain, is a leading cause of death worldwide. Its main cause is atherosclerosis, a disease of the arteries characterized by the deposition of plaques of fatty material on the inner artery walls. Multiple proteins involved in the inflammation response have been identified as diagnosing biomarkers of ischemic stroke. One of these is lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme that can hydrolyze circulating oxidized phospholipids, generating proinflammatory lysophosphatidylcholine and promoting the development of atherosclerosis. In the last two decades, a number of studies have revealed that both the concentration and the activity of Lp-PLA2 are independent biomarkers of ischemic stroke. The US Food and Drug Administration (FDA) has approved two tests to determine Lp-PLA2 mass and activity for predicting stroke. In this review, we summarize the biological properties of Lp-PLA2, the detection sensitivity and limitations of Lp-PLA2 measurement, the clinical significance and association of Lp-PLA2 in ischemic stroke, and the prospects of therapeutic inhibition of Lp-PLA2 as an intervention and treatment.


Assuntos
Aterosclerose , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , 1-Alquil-2-acetilglicerofosfocolina Esterase/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterase/uso terapêutico , Acidente Vascular Cerebral/etiologia , Aterosclerose/metabolismo , Biomarcadores , Fatores de Risco
14.
FASEB J ; 36(12): e22630, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36315163

RESUMO

The endothelium, a crucial homeostatic organ, regulates vascular permeability and tone. Under physiological conditions, endothelial stimulation induces vasodilator endothelial nitric oxide (eNO) release and prevents adhesion molecule accessibility and leukocyte adhesion and migration into vessel walls. Endothelium dysfunction is a principal event in cardiovascular disorders, including atherosclerosis. Minimal attention is given to an important endothelial cell structure, the endothelial glycocalyx (GCX), a negatively charged heterogeneous polysaccharide that serves as a protective covering for endothelial cells and enables endothelial cells to transduce mechanical stimuli into various biological and chemical activities. Endothelial GCX shedding thus plays a role in endothelial dysfunction, for example by increasing vascular permeability and decreasing vessel tone. Consequently, there is increasing interest in developing therapies that focus on GCX repair to limit downstream endothelium dysfunction and prevent further downstream cardiovascular events. Here, we present diosmin (3',5,7-trihydroxy-4'-methoxyflavone-7-rhamnoglucoside), a flavone glycoside of diosmetin, which downregulates adhesive molecule expression, decreases inflammation and capillary permeability, and upregulates eNO expression. Due to these pleiotropic effects of diosmin on the vasculature, a possible unidentified mechanism of action is through GCX restoration. We hypothesize that diosmin positively affects GCX integrity along with GCX-related endothelial functions. Our hypothesis was tested in a partial ligation left carotid artery (LCA) mouse model, where the right carotid artery was the control for each mouse. Diosmin (50 mg/kg) was administered daily for 7 days, 72 h after ligation. Within the ligated mice LCAs, diosmin treatment elevated the activated eNO synthase level, inhibited inflammatory cell uptake, decreased vessel wall thickness, increased vessel diameter, and increased GCX coverage of the vessel wall. ELISA showed a decrease in hyaluronan concentration in plasma samples of diosmin-treated mice, signifying reduced GCX shedding. In summary, diosmin supported endothelial GCX integrity, to which we attribute diosmin's preservation of endothelial function as indicated by attenuated expression of inflammatory factors and restored vascular tone.


Assuntos
Aterosclerose , Diosmina , Camundongos , Animais , Glicocálix/metabolismo , Diosmina/farmacologia , Diosmina/metabolismo , Células Endoteliais/metabolismo , Aterosclerose/metabolismo , Óxido Nítrico/metabolismo , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/metabolismo , Endotélio Vascular/metabolismo
15.
Int J Mol Sci ; 23(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36292963

RESUMO

Atherosclerosis is a hallmark of cardiovascular disease, and lifestyle strongly impacts its onset and progression. Nutrients have been shown to regulate the miR-17/92 cluster, with a role in endothelial function and atherosclerosis. Choline, betaine, and L-carnitine, found in animal foods, are metabolized into trimethylamine (TMA) by the gut microbiota. TMA is then oxidized to TMAO, which has been associated with atherosclerosis. Our aim was to investigate whether TMAO modulates the expression of the miR-17/92 cluster, along with the impact of this modulation on the expression of target genes related to atherosclerosis and inflammation. We treated HepG-2 cells, THP-1 cells, murine liver organoids, and human peripheral mononuclear cells with 6 µM of TMAO at different timepoints. TMAO increased the expression of all analyzed members of the cluster, except for miR-20a-5p in murine liver organoids and primary human macrophages. Genes and protein levels of SERPINE1 and IL-12A increased. Both have been associated with atherosclerosis and cardiovascular disease (CDVD) and are indirectly modulated by the miR-17-92 cluster. We concluded that TMAO modulates the expression of the miR-17/92 cluster and that such modulation could promote inflammation through IL-12A and blood clotting through SERPINE1 expression, which could ultimately promote atherosclerosis and CVD.


Assuntos
Aterosclerose , Doenças Cardiovasculares , MicroRNAs , Humanos , Camundongos , Animais , Betaína/metabolismo , Metilaminas/metabolismo , Aterosclerose/metabolismo , Colina/metabolismo , Carnitina/metabolismo , MicroRNAs/genética , Inflamação/genética
16.
Int J Mol Sci ; 23(20)2022 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-36293305

RESUMO

Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of atherosclerosis, epigenetic modifications influence gene expression. As such, epigenetic modifications are an adaptive response to endogenous and exogenous factors that lead to altered gene expression by methylation and acetylation reactions of different substrates and the action of noncoding RNA including microRNAs (miRNAs). Epigenetic remodeling modulates cell biology in both physiological and physiopathological conditions. DNA and histone modification have been identified to have a crucial role in the progression of atherosclerosis. However, the potential role of miRNAs in hyperHcy (HHcy)-related atherosclerosis disease remains poorly explored and might be essential as well. There is no review available yet summarizing the contribution of miRNAs to hyperhomocystein-mediated atherogenicity or their potential as therapeutic targets even though their important role has been described in numerous studies. Specifically, downregulation of miR-143 or miR-125b has been shown to regulate VSCMs proliferation in vitro. In preclinical studies, downregulation of miR-92 or miR195-3p has been shown to increase the accumulation of cholesterol in foam cells and increase macrophage inflammation and atherosclerotic plaque formation, respectively. Another preclinical study found that there is a reciprocal regulation between miR-148a/152 and DNMT1 in Hcy-accelerated atherosclerosis. Interestingly, a couple of studies have shown that miR-143 or miR-217 may be used as potential biomarkers in patients with HHcy that may develop atherosclerosis. Moreover, the current review will also update current knowledge on miRNA-based therapies, their challenges, and approaches to deal with Hcy-induced atherosclerosis.


Assuntos
Aterosclerose , Hiper-Homocisteinemia , MicroRNAs , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , MicroRNAs/metabolismo , Epigênese Genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Biomarcadores , Homocisteína/metabolismo
17.
Int J Mol Sci ; 23(20)2022 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-36293399

RESUMO

Atherosclerosis (AS), the main cause of many cardiovascular diseases (CVDs), is a progressive inflammatory disease characterized by the accumulation of lipids, fibrous elements, and calcification in the innermost layers of arteries. The result is the thickening and clogging of these vessel walls. Several cell types are directly involved in the pathological progression of AS. Among them, platelets represent the link between AS, inflammation, and thrombosis. Indeed, besides their pivotal role in hemostasis and thrombosis, platelets are key mediators of inflammation at injury sites, where they act by regulating the function of other blood and vascular cell types, including endothelial cells (ECs), leukocytes, and vascular smooth muscle cells (VSMCs). In recent years, increasing evidence has pointed to a central role of platelet-derived extracellular vesicles (P-EVs) in the modulation of AS pathogenesis. However, while the role of platelet-derived microparticles (P-MPs) has been significantly investigated in recent years, the same cannot be said for platelet-derived exosomes (P-EXOs). For this reason, this reviews aims at summarizing the isolation methods and biological characteristics of P-EXOs, and at discussing their involvement in intercellular communication in the pathogenesis of AS. Evidence showing how P-EXOs and their cargo can be used as biomarkers for AS is also presented in this review.


Assuntos
Aterosclerose , Micropartículas Derivadas de Células , Exossomos , Trombose , Humanos , Exossomos/metabolismo , Micropartículas Derivadas de Células/metabolismo , Células Endoteliais/metabolismo , Aterosclerose/metabolismo , Inflamação/metabolismo , Trombose/metabolismo , Biomarcadores/metabolismo , Mediadores da Inflamação/metabolismo , Lipídeos
18.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293483

RESUMO

Natriuretic peptide receptor 1 (NPR1) serves as a modulator of vascular endothelial homeostasis. Interactions between monocytes and endothelial cells may initiate endothelium dysfunction, which is known as an early hallmark of atherosclerosis. In this study, we performed RNA-sequencing analysis for the aorta of Npr1 knockout (Npr1+/-) mice and found that differentially expressed genes were significantly related to cell adhesion. This result was supported by an increased expression of intercellular adhesion molecule 1 (ICAM-1) in the aortic endothelium of Npr1+/- mice. Moreover, we observed that the knockdown of NPR1 increased ICAM-1 expression and promoted THP-1 monocyte adhesion to human umbilical vein endothelial cells (HUVECs). NPR1 overexpression decreased ICAM-1 expression and inhibited the adhesion of monocytes to HUVECs treated by TNF-α (a cell adhesion inducer). Further analysis showed that adhesion-related genes were enriched in the focal adhesion signaling pathway, in which integrin beta 4 (Itgb4) was determined as a key gene. Notably, ITGB4 expression increased in vascular endothelium of Npr1+/- mice and in NPR1-knockdown HUVECs. The deficiency of ITGB4 decreased ICAM-1 expression and attenuated monocyte adhesion to NPR1-knockdown endothelial cells. Additionally, a reduced NPR1 and an increased ITGB4 expression level were found in an atherosclerosis mouse model. In conclusion, our findings demonstrate that NPR1 deficiency increases vascular endothelial cell adhesion by stimulating ITGB4 expression, which may contribute to the development of atherosclerosis.


Assuntos
Aterosclerose , Molécula 1 de Adesão Intercelular , Humanos , Camundongos , Animais , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Endotélio Vascular/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Monócitos/metabolismo , Adesão Celular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Integrinas/metabolismo , RNA/metabolismo
19.
Cells ; 11(20)2022 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-36291054

RESUMO

Retinoic acid signaling plays an important role in regulating lipid metabolism and inflammation. However, the role of retinoic acid receptor alpha (RARα) in atherosclerosis remains to be determined. In the current study, we investigated the role of macrophage RARα in the development of atherosclerosis. Macrophages isolated from myeloid-specific Rarα-/- (RarαMac-/-) mice showed increased lipid accumulation and inflammation and reduced cholesterol efflux compared to Rarαfl/fl (control) mice. All-trans retinoic acid (AtRA) induced ATP-binding cassette subfamily A member 1 (Abca1) and Abcg1 expression and cholesterol efflux in both RarαMac-/- mice and Rarαfl/fl mice. In Ldlr-/- mice, myeloid ablation of RARα significantly reduced macrophage Abca1 and Abcg1 expression and cholesterol efflux, induced inflammatory genes, and aggravated Western diet-induced atherosclerosis. Our data demonstrate that macrophage RARα protects against atherosclerosis, likely via inducing cholesterol efflux and inhibiting inflammation.


Assuntos
Aterosclerose , Colesterol , Dieta Ocidental , Macrófagos , Receptor alfa de Ácido Retinoico , Animais , Camundongos , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/metabolismo , Colesterol/metabolismo , Inflamação/genética , Macrófagos/metabolismo , Receptor alfa de Ácido Retinoico/genética , Receptor alfa de Ácido Retinoico/metabolismo , Tretinoína/farmacologia , Tretinoína/metabolismo , Dieta Ocidental/efeitos adversos , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Camundongos Knockout
20.
Biochem Biophys Res Commun ; 635: 120-127, 2022 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-36265285

RESUMO

Macrophage polarization plays a crucial role in atherosclerosis (AS), which is closely associated with energy metabolism. However, the underlying mechanism remains elusive. Hepatoma-derived growth factor (HDGF) has been reported to promote tumor metastasis via energy metabolism reprogramming. In this study, we aimed to investigate the role and underlying mechanism of HDGF in regulating macrophage polarization and AS. Our results suggested the elevated expression of HDGF in aortas from atherosclerotic patients and ApoeKO mice, as well as M1 macrophages. The specific deficiency of HDGF in macrophages resulted in a significant reduction of plaque area, inflammation and M1 macrophages content in ApoeKO mouse model of AS. Consistent with the in vivo data, the specific deficiency of HDGF attenuated the inflammation, glycolysis, and lipids accumulation in M1 macrophages, and rescued the mitochondrial dysfunction. Mechanistically, HDGF plays a crucial role in atherogenesis by regulating the M1 macrophages polarization through energy metabolism reprogramming. The expression level of methyltransferase Mettl3 elevated significantly in M1 macrophages, which contributed to enhancing mRNA stability and protein expression of HDGF via N6-methyladenosine (m6A) RNA methylation. Taken together, our study revealed a novel mechanism underlying the macrophage polarization, which may be a potential therapy for AS.


Assuntos
Aterosclerose , Animais , Camundongos , Aterosclerose/metabolismo , Metabolismo Energético , Inflamação/patologia , Macrófagos/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo , RNA/metabolismo , Camundongos Knockout para ApoE
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