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1.
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
2.
Genes (Basel) ; 13(11)2022 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-36360235

RESUMO

Hypertension is an independent risk factor for atherosclerosis. However, few models of hypertensive atherosclerosis have been established in medical research. In this study, we crossed the ApoE knockout (ApoE-KO; ApoE-/-) atherosclerotic mouse model with the NOS3 knockout (NOS3-KO; NOS3-/-) hypertensive mouse model to establish an ApoE/NOS3 double knockout (ApoE/NOS3-KO; ApoE/NOS3-/-) hypertensive atherosclerosis mouse model. We found that ApoE/NOS3-/- mice reproduced normally, had a blood pressure of 133.00 ± 3.85 mmHg, and developed hypertensive fundus retinopathy and hypertensive nephropathy. In addition, serum total cholesterol (TC) and low-density lipoprotein (LDL) levels in the blood were abnormally elevated, steatosis was observed in the liver cells, and atherosclerotic lesions were observed in the aortic vessels in ApoE/NOS3-/- adult mice. In conclusion, ApoE/NOS3-/- adult mice are a satisfactory model of hypertension and atherosclerosis and can be utilized for studies on cardiovascular diseases.


Assuntos
Aterosclerose , Doenças Cardiovasculares , Hipertensão , Camundongos , Animais , Camundongos Knockout para ApoE , Camundongos Knockout , Aterosclerose/genética , Apolipoproteínas E/genética , Hipertensão/genética , Óxido Nítrico Sintase Tipo III
3.
Oxid Med Cell Longev ; 2022: 2520348, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36425057

RESUMO

Influenza virus infection is one of the strongest pathogenic factors for the development of acute lung injury (ALI)/ acute respiratory distress syndrome (ARDS). However, the underlying cellular and molecular mechanisms have not been clarified. In this study, we aim to investigate whether melatonin modulates macrophage polarization, oxidative stress, and pyroptosis via activating Apolipoprotein E/low-density lipoprotein receptor (ApoE/LDLR) pathway in influenza A-induced ALI. Here, wild-type (WT) and ApoE-/- mice were instilled intratracheally with influenza A (H3N2) and injected intraperitoneally with melatonin for 7 consecutive days. In vitro, WT and ApoE-/- murine bone marrow-derived macrophages (BMDMs) were pretreated with melatonin before H3N2 stimulation. The results showed that melatonin administration significantly attenuated H3N2-induced pulmonary damage, leukocyte infiltration, and edema; decreased the expression of proinflammatory M1 markers; enhanced anti-inflammatory M2 markers; and switched the polarization of alveolar macrophages (AMs) from M1 to M2 phenotype. Additionally, melatonin inhibited reactive oxygen species- (ROS-) mediated pyroptosis shown by downregulation of malonaldehyde (MDA) and ROS levels as well as inhibition of the NLRP3/GSDMD pathway and lactate dehydrogenase (LDH) release. Strikingly, the ApoE/LDLR pathway was activated when melatonin was applied in H3N2-infected macrophages and mice. ApoE knockout mostly abrogated the protective impacts of melatonin on H3N2-induced ALI and its regulatory ability on macrophage polarization, oxidative stress, and pyroptosis. Furthermore, recombinant ApoE3 (re-ApoE3) inhibited H3N2-induced M1 polarization of BMDMs with upregulation of MT1 and MT2 expression, but re-ApoE2 and re-ApoE4 failed to do this. Melatonin combined with re-ApoE3 played more beneficial protective effects on modulating macrophage polarization, oxidative stress, and pyroptosis in H3N2-infected ApoE-/- BMDMs. Our study indicated that melatonin attenuated influenza A- (H3N2-) induced ALI by inhibiting the M1 polarization of pulmonary macrophages and ROS-mediated pyroptosis via activating the ApoE/LDLR pathway. This study suggested that melatonin-ApoE/LDLR axis may serve as a novel therapeutic strategy for influenza virus-induced ALI.


Assuntos
Lesão Pulmonar Aguda , Melatonina , Infecções por Orthomyxoviridae , Animais , Camundongos , Lesão Pulmonar Aguda/tratamento farmacológico , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/virologia , Apolipoproteína E3/farmacologia , Apolipoproteínas E/metabolismo , Vírus da Influenza A Subtipo H3N2 , Macrófagos/metabolismo , Melatonina/uso terapêutico , Camundongos Knockout para ApoE , Piroptose , Espécies Reativas de Oxigênio/metabolismo , Infecções por Orthomyxoviridae/tratamento farmacológico
4.
Nutrients ; 14(20)2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36297020

RESUMO

Capsaicin is a pungent alkaloid abundantly present in peppers with outstanding biological activities, including the anti-atherosclerosis effect. Previous studies revealed that gut microbiota played an important role in the beneficial effects of capsaicin, but whether it is essential for the anti-atherosclerosis effect of capsaicin is unclear. This study evaluated the anti-atherosclerosis effect of capsaicin in ApoE-/- mice and further explored the role of depleting gut microbiota in the improvement of atherosclerosis. The results showed that capsaicin administration could prevent the development of atherosclerosis and improve serum lipids and inflammation, while antibiotic intervention abolished the alleviation of atherosclerosis by capsaicin. In addition, capsaicin administration could significantly increase the abundance of Turicibacter, Odoribacter, and Ileibacterium in feces, and decrease the abundance of deoxycholic acid, cholic acid, hypoxanthine, and stercobilin in cecal content. Our study provides evidence that gut microbiota plays a critical role in the anti-atherosclerosis effect of capsaicin.


Assuntos
Aterosclerose , Capsaicina , Microbioma Gastrointestinal , Animais , Camundongos , Antibacterianos/farmacologia , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Aterosclerose/microbiologia , Capsaicina/farmacologia , Ácido Cólico , Ácido Desoxicólico , Dieta Hiperlipídica/efeitos adversos , Hipoxantinas , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
5.
Biochem Biophys Res Commun ; 634: 138-144, 2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36242920

RESUMO

In recent years, abdominal aortic aneurysm (AAA) lesions have become one of the important diseases that threaten public health. Related studies have confirmed that the occurrence of abdominal aortic aneurysms is related to inflammatory stress, cell apoptosis, and elastic fiber degradation. DDX3x is thought to interact with inflammasomes such as NLRP3 to aggravate the process of the inflammatory response, but its role in the occurrence of AAA remains unclear. Since DDX3x is indispensable in animal embryonic growth, we used an adeno-associated virus to construct gene-overexpressing mice to induce aneurysm development through AngII infusion. The results indicated that the incidence of aneurysms, inflammatory cell infiltration, vascular smooth muscle cell transformation, and oxidative stress levels were significantly increased under the condition of DDX3x overexpression. At the signaling level, activation of the AKT pathway exacerbates aneurysm formation. Taken together, we believe that DDX3x plays a key role in the development of aneurysms and may be a new target for the treatment of aneurysm progression.


Assuntos
Aneurisma da Aorta Abdominal , Camundongos , Animais , Aneurisma da Aorta Abdominal/patologia , Camundongos Knockout para ApoE , Aorta Abdominal/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Camundongos Knockout , Angiotensina II/metabolismo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , RNA Helicases DEAD-box/genética , RNA Helicases DEAD-box/metabolismo
6.
Arterioscler Thromb Vasc Biol ; 42(12): e291-e310, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36252109

RESUMO

BACKGROUND: Erythrocytes (red blood cells) participate in the control of vascular NO bioavailability. The purpose of this study was to determine whether and how genetic deletion of ARG1 (arginase-1) affects vascular smooth muscle cell NO signaling, osteoblastic differentiation, and atherosclerotic lesion calcification. METHODS: Atherosclerosis-prone mice with conditional, erythrocyte-restricted deletion of ARG1 (apoE-/- red blood cell.ARG1 knockout) were generated and vascular calcification studied using molecular imaging of the osteogenic activity agent OsteoSense, Alizarin staining or immunohistochemistry, qPCR of osteogenic markers and ex vivo assays. RESULTS: Atherosclerotic lesion size at the aortic root did not differ, but calcification was significantly more pronounced in apoE-/- mice lacking erythrocyte ARG1. Incubation of murine and human VSMCs with lysed erythrocyte membranes from apoE-/- red blood cell. ARG1-knockout mice accelerated their osteogenic differentiation, and mRNA transcripts of osteogenic markers decreased following NO scavenging. In addition to NO signaling via sGC (soluble guanylyl cyclase), overexpression of GSNOR (S-nitrosoglutathione reductase) enhanced degradation of S-nitrosoglutathione to glutathione and reduced protein S-nitrosation of HSP (heat shock protein)-70 were identified as potential mechanisms of vascular smooth muscle cell calcification in mice lacking ARG1 in erythrocytes, and calcium phosphate deposition was enhanced by heat shock and prevented by GSNOR inhibition. Messenger RNA levels of enzymes metabolizing the arginase products L-ornithine and L-proline also were elevated in VSMCs, paralleled by increased proliferation, myofibroblast marker and collagen type 1 expression. CONCLUSIONS: Our findings support an important role of erythrocyte ARG1 for NO bioavailability and L-arginine metabolism in VSMCs, which controls atherosclerotic lesion composition and calcification.


Assuntos
Arginase , Aterosclerose , Calcificação Vascular , Animais , Humanos , Camundongos , Arginase/genética , Aterosclerose/patologia , Células Cultivadas , Eritrócitos/metabolismo , Miócitos de Músculo Liso/metabolismo , Osteogênese/genética , Oxirredutases/metabolismo , Calcificação Vascular/patologia , Camundongos Knockout para ApoE , Óxido Nítrico/metabolismo
7.
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
8.
JCI Insight ; 7(20)2022 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-36278486

RESUMO

Vascular smooth muscle cells (SMCs) are heterogeneous, and their differential responses to vascular injury are not well understood. To address this question, we performed single-cell analysis of vascular cells to a ligation injury in mouse carotid arteries after 3 days. While endothelial cells had a homogeneous activation of mesenchymal genes, less than 30% of SMCs responded to the injury and generated 2 distinct clusters - i.e., proinflammatory SMCs and stress-responsive SMCs. Proinflammatory SMCs were enriched with high levels of inflammatory markers such as vascular cell adhesion molecule-1 while stress-responsive SMCs overexpressed heat shock proteins. Trajectory analysis suggested that proinflammatory SMCs were potentially derived from a specific subpopulation of SMCs. Ligand-receptor pair analysis showed that the interaction between macrophages and proinflammatory SMCs was the major cell-cell communication among all cell types in the injured arteries. In vitro coculture demonstrated that VCAM1+ SMCs had a stronger chemotactic effect on macrophage recruitment than VCAM1- SMCs. Consistently, the number of VCAM1+ SMCs significantly increased in injured arteries and atherosclerotic lesions of ApoE-/- mice and human arteries. These findings provide insights at the single-cell level on the distinct patterns of endothelial cells and SMC responses to vascular injury.


Assuntos
Células Endoteliais , Lesões do Sistema Vascular , Camundongos , Humanos , Animais , Células Endoteliais/metabolismo , Lesões do Sistema Vascular/metabolismo , Músculo Liso Vascular , Molécula 1 de Adesão de Célula Vascular/metabolismo , Ligantes , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Proteínas de Choque Térmico/metabolismo
9.
Int J Biol Sci ; 18(14): 5230-5240, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36147474

RESUMO

Checkpoint immunotherapy is capable of unleashing T cells for controlling tumor, whereas it is destroyed by immunosuppressive myeloid cell. Apoprotein E (APOE) refers to a ligand in terms of the members of low-density lipoprotein (LDL) receptor family for mediating Apoprotein B-involving atherogenic lipoprotein clearance. Besides, tumor-infiltration macrophage can express APOE. The present study reported Apoe-/- mice to exhibit higher resistance toward the development of three types of carcinomas as compared with mice with wild type and to have greater responses to αPD-1 (anti-PD-1) immunotherapy. Moreover, treatment by exploiting APOE inhibitor (COG 133TFA, αAPOE) was capable of curbing tumor development and fostering regression if in combination of αPD-1. According to single-cell RNA sequencing (scRNA-seq), Apoe deletion was correlated with the decline of C1QC+ and CCR2+ macrophage within tumor infiltration, and mass spectrometry results noticeably showed down-regulated the number of M2 macrophages as well. Furthermore, APOE expression in cancer patients resistant to αPD-1 treatment significantly exceeded that in the sensitive group. For this reason, APOE is likely to be targeted for modifying tumor macrophage infiltrate and augmenting checkpoint immunotherapy.


Assuntos
Apolipoproteínas E , Apoproteínas , Inibidores de Checkpoint Imunológico , Neoplasias , Animais , Apolipoproteínas E/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Ligantes , Lipoproteínas LDL , Camundongos , Camundongos Knockout para ApoE , Neoplasias/tratamento farmacológico , Microambiente Tumoral
10.
Biomolecules ; 12(9)2022 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-36139044

RESUMO

2-Hydroxypropyl-beta-cyclodextrin (2HPßCD) is able to bind and solubilize unesterified cholesterol and may therefore be able to reverse the deposition of cholesterol in macrophages within the aortic vessel wall, a hallmark of atherosclerotic cardiovascular disease. However, conflicting results regarding the potential of 2HPßCD to induce regression of established atherosclerotic lesions have been described. In the current study, we therefore also investigated the ability of 2HPßCD to stimulate cholesterol removal from macrophage foam cells in vitro and induce the regression of established atherosclerotic lesions in apolipoprotein E knockout (APOE KO) mice. In vitro studies using murine thioglycollate-elicited peritoneal macrophages verified that 2HPßCD is able to induce cholesterol efflux from macrophages in an ATP-binding cassette transporter-independent manner. Switching Western-type-diet-fed APOE KO mice with established atherosclerotic lesions back to a chow diet was associated with a reduction in the hypercholesterolemia extent and an increase in the absolute lesion size and plaque collagen-to-macrophage ratio. Importantly, parallel subcutaneous administration of 2HPßCD was not able to prevent the diet-switch-associated lesion growth or induce atherosclerosis regression. Although in our hands, 2HPßCD does effectively stimulate cellular cholesterol efflux from macrophages, we do not consider it worthwhile to further pursue 2HPßCD as therapeutic moiety in the atherosclerosis regression context.


Assuntos
Aterosclerose , Tioglicolatos , 2-Hidroxipropil-beta-Ciclodextrina , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/metabolismo , Colesterol/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE
11.
Biomolecules ; 12(9)2022 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-36139057

RESUMO

Lipid transporter protein apolipoprotein E (APOE) has contributed to functional studies of various organ functions. Animals with ApoE knockout (KO) have been used to study atherosclerosis and hyperlipidemia while an increasing number of researchers have recently focused on the association of ApoE with hearing loss. A study found that ApoE KO mice experience sensorineural hearing loss and hair cell loss, but the exact mechanism is unclear. To explore the potential relationship between ApoE and hearing loss, we used HEI-OC1 cells (House Ear Institute-Organ of Corti) with Corti apparatus properties to reveal cell changes after ApoE knockout by combined transcriptome and metabolomic analysis. We found that glutamate deficiency, caused by reduced expression of glutamine transporter proteins, was a key correlate of basal metabolism and that inadequate glutamate causes apoptosis by reducing the cells' resistance to external damage. Our study provides a reference mechanism for hearing loss due to ApoE KO.


Assuntos
Vias Auditivas , Perda Auditiva , Animais , Apoptose , Glutamatos , Glutamina , Camundongos , Camundongos Knockout para ApoE
12.
Cells ; 11(18)2022 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-36139452

RESUMO

Genetic variants in transmembrane 6 superfamily member 2 (TM6SF2), such as E167K, are associated with atherosclerotic cardiovascular disease (ASCVD). Chronic inflammation and lipid-laden macrophage foam cell formation are the central pathogeneses in the development of atherosclerosis. This study was undertaken to illustrate the biological function of TM6SF2 in macrophages and its role during atherosclerosis development. We generated myeloid cell-specific Tm6sf2 knockout mice on ApoE-deficient background (LysM Cre+/Tm6sf2fl/fl/ApoE-/-, TM6 mKO) with littermate LysM Cre-/Tm6sf2fl/fl/ApoE-/- (Control) mice as controls. Mice were fed a Western diet for 12 weeks to induce atherosclerosis. Myeloid Tm6sf2 deficiency inhibited atherosclerosis and decreased foam cells in the plaques without changing the plasma lipid profile. RNA sequencing of bone marrow-derived macrophages (BMDMs) from TM6 mKO mice demonstrated the downregulation of genes associated with inflammation, cholesterol uptake, and endoplasmic reticulum (ER) stress. TM6SF2 was upregulated by oxidized low-density lipoprotein (oxLDL) in macrophages. Silencing TM6SF2 in THP-1-derived macrophages and Tm6sf2 deficiency in BMDMs reduced inflammatory responses and ER stress and attenuated cholesterol uptake and foam cell formation, while the overexpression of TM6SF2 showed opposite effects. In conclusion, myeloid TM6SF2 deficiency inhibits atherosclerosis development and is a potential therapeutic target for the treatment of atherogenesis.


Assuntos
Aterosclerose , Proteínas de Membrana , Animais , Aterosclerose/genética , Colesterol , Inflamação , Lipoproteínas LDL , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout para ApoE
13.
DNA Cell Biol ; 41(10): 871-878, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36070556

RESUMO

UFMylation is a novel ubiquitin-like system that deals with complex and fine-tuned cellular activities and is closely related to endoplasmic reticulum stress. Our previous study indicated that UFMylation is activated in vascular remodeling models. However, the role of UFMylation in atherosclerosis (AS) is unclear. In this study, we investigated changes in UFMylation in ApoE knockout (ApoE-KO) mice. We found that UFMylation was significantly activated in ApoE-KO mice fed a high-fat diet for 46 weeks. Consistently we observed that vascular smooth muscle cells (VSMCs) treated with oxidized low-density lipoprotein (oxLDL) showed UFMylation activation in a time-dependent manner. UFM1-overexpressing mice were generated using transgenic (Tg) technique and bred with ApoE-KO mice to generate ApoE-KO/UFM1-Tg mice. We found that the degree of AS did not vary compared with that of the control. Similarly, overexpression of active UFM1 failed to alter oxLDL-induced proliferation of VSMCs. These findings indicate that UFMylation is activated in AS, but overexpression of UFM1 does not alter the development of AS in ApoE-KO mice.


Assuntos
Aterosclerose , Camundongos , Animais , Camundongos Knockout para ApoE , Aterosclerose/genética , Lipoproteínas LDL , Apolipoproteínas E/genética , Ubiquitinas , Camundongos Knockout , Camundongos Endogâmicos C57BL
14.
J Cell Mol Med ; 26(20): 5267-5276, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36098213

RESUMO

Hypercholesterolemia exacerbates autoimmune response and accelerates the progression of several autoimmune disorders, but the mechanistic basis is not well understood. We recently demonstrated that hypercholesterolemia is associated with increased serum extracellular DNA levels secondary to a defect in DNase-mediated clearance of DNA. In this study, we tested whether the impaired DNase response plays a causal role in enhancing anti-nuclear antibody levels and renal immune complex deposition in an Apoe-/- mouse model of hypercholesterolemia. We demonstrate that hypercholesterolemic mice have enhanced anti-ds-DNA and anti-nucleosome antibody levels which is associated with increased immune complex deposition in the renal glomerulus. Importantly, treatment with DNase1 led to a decrease in both the autoantibody levels as well as renal pathology. Additionally, we show that humans with hypercholesterolemia have decreased systemic DNase activity and increased anti-nuclear antibodies. In this context, our data suggest that recombinant DNase1 may be an attractive therapeutic strategy to lower autoimmune response and disease progression in patients with autoimmune disorders associated with concomitant hypercholesterolemia.


Assuntos
Doenças Autoimunes , Desoxirribonucleases , Hipercolesterolemia , Lúpus Eritematoso Sistêmico , Animais , Complexo Antígeno-Anticorpo , Autoanticorpos , DNA , Desoxirribonucleases/metabolismo , Humanos , Hipercolesterolemia/genética , Camundongos , Camundongos Knockout para ApoE
15.
Int Immunopharmacol ; 112: 109177, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36049351

RESUMO

BACKGROUND: Aortic dissection (AD) is a fatal vascular disease in absence of effective pharmaceutical therapy. Adenosine monophosphate-activated protein kinase α (AMPKα) plays a critical role in various cardiovascular diseases. Whether AMPKα is involved in the pathogenesis of aortic dissection remains unknown. We aimed to determine whether activation of AMPKα prevents the formation of AD. METHODS AND RESULTS: Reduced expression of phosphorylated AMPKα (Thr172) and exacerbated phenotypic switching were observed in human aortic tissues from aortic dissection patients compared with those in tissues from controls. In vivo, the formation of aortic dissection in ApoE-/- mice was successfully induced by continuous infusion of angiotensin II (AngII) for two weeks, characterized by the activation of vascular inflammation, infiltration of macrophages and phenotypic switching of vascular smooth muscle cells (VSMCs). rAAV2-mediated overexpression of constitutively active AMPKα (CA-AMPKα) enhanced the expression of phosphorylated AMPKα (Thr172) and attenuated AngII-induced occurrence of aortic dissection by suppressing the infiltration of macrophages, activation of vascular inflammation and phenotypic switching of VSMCs. The pathogenesis above was conversely exacerbated by rAAV2-mediated overexpression of dominant negative AMPKα2 (DN-AMPKα). In vitro, we demonstrated that the administration of an AMPK agonist (AICAR) or transfection of CA-AMPKα induced the activation of AMPKα and then ameliorated AngII-induced phenotypic switching in the VSMCs and inflammation in the bone marrow-derived macrophages (BMDMs). This could be reversed by the addition of AMPK inhibitor compound C or transfection of DN-AMPKα. CONCLUSION: Impaired activation of AMPKα may increase the susceptibility to aortic dissection. Our findings verified the protective effects of AMPKα on the formation of aortic dissection and may provide evidence for clinical prevention or treatment.


Assuntos
Proteínas Quinases Ativadas por AMP , Aneurisma Dissecante , Animais , Humanos , Camundongos , Monofosfato de Adenosina/farmacologia , Proteínas Quinases Ativadas por AMP/metabolismo , Aneurisma Dissecante/metabolismo , Aneurisma Dissecante/patologia , Angiotensina II/metabolismo , Células Cultivadas , Inflamação/metabolismo , Músculo Liso Vascular , Miócitos de Músculo Liso , Camundongos Knockout para ApoE
16.
Cells ; 11(18)2022 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-36139494

RESUMO

Inflammation, oxidative stress, and copper (Cu) play an important role in cardiovascular disease, including atherosclerosis. We previously reported that cytosolic Cu chaperone antioxidant-1 (Atox1) translocates to the nucleus in response to inflammatory cytokines or exogenous Cu and that Atox1 is localized at the nucleus in the endothelium of inflamed atherosclerotic aorta. However, the roles of nuclear Atox1 and their function are poorly understood. Here we showed that Atox1 deficiency in ApoE-/- mice with a Western diet exhibited a significant reduction of atherosclerotic lesion formation. In vitro, adenovirus-mediated overexpression of nuclear-targeted Atox1 (Ad-Atox1-NLS) in cultured human endothelial cells (ECs) increased monocyte adhesion and reactive oxygen species (ROS) production compared to control cells (Ad-null). To address the underlying mechanisms, we performed genome-wide mapping of Atox1-regulated targets in ECs, using an unbiased systemic approach integrating sequencing data. Combination of ChIP-Seq and RNA-Seq analyses in ECs transfected with Ad-Atox1-NLS or Ad-null identified 1387 differentially expressed genes (DEG). Motif enrichment assay and KEGG pathway enrichment analysis revealed that 248 differentially expressed genes, including inflammatory and angiogenic genes, were regulated by Atox1-NLS, which was then confirmed by real-time qPCR. Among these genes, functional analysis of inflammatory responses identified CD137, CSF1, and IL5RA as new nuclear Atox1-targeted inflammatory genes, while CD137 is also a key regulator of Atox1-NLS-induced ROS production. These findings uncover new nuclear Atox1 downstream targets involved in inflammation and ROS production and provide insights into the nuclear Atox1 as a potential therapeutic target for the treatment of inflammatory diseases such as atherosclerosis.


Assuntos
Aterosclerose , Cobre , Animais , Aterosclerose/genética , Cobre/metabolismo , Proteínas de Transporte de Cobre , Citocinas/metabolismo , Células Endoteliais/metabolismo , Humanos , Inflamação/genética , Camundongos , Camundongos Knockout para ApoE , Chaperonas Moleculares/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transcriptoma
18.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 38(2): 137-142, 2022 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-36031571

RESUMO

Objective: To investigate the effects of 6 weeks of aerobic exercise on the sarcoplasmic reticulum calcium regulatory proteins in skeletal muscle of apolipoprotein E (ApoE) knockout mice fed by high-fat diet. Methods: There were a total of twenty five 9-week-old ApoE knockout mice (ApoE knockout mice, ApoE KO), five of which were selected randomly for the maximum running speed test. The running speed would be increased by 1.2 m/min every 3 min after a 5-min duration of initial speed of 4.8 m/min without slope until exhaustion, then the final speed was set as maximal speed, and the test result of the maximum running speed was (27.0±2.4)m/min. The remaining 20 ApoE KO mice were randomly divided into ApoE KO mouse high-fat diet group (KO) and ApoE KO mouse high-fat diet + aerobic exercise group (KE), 10 mice per group. Ten 9-week-old wild-type C57BL/6J mice were used as a blank control group (wild-type, WT). High fat diet composition: fat content was 21% (w/w) and cholesterol content was 1.5% (w/w). Exercise intervention was initiated 1 week after adaptive training in the KE group with an exercise protocol consisting of 40% maximal running speed (10.8 m/min), 40 min/d and a frequency of 3 d/w for a total of 6 weeks. All mice were anesthetized and sacrificed by cardiac puncture then bilateral gastrocnemius muscles were isolated immediately 48 h after the final exercise. Skeletal muscle Ca2+ concentration was detected by visible light colorimetry; the expression levels of RyR, CaM, CaMK Ⅱ, SERCA1 and SERCA2, which are calcium regulated proteins of sarcoplasmic reticulum, in mouse skeletal muscle, was detected by Western blotting. Results: Compared with WT mice, the Ca2+ concentration, the expression levels of the sarcoplasmic reticulum calcium releasing proteins RyR, CaMKⅡ, and the calcium recycling proteins SERCA1 and SERCA2 were decreased significantly in skeletal muscle of the KO mice (P<0.05, P<0.01), while the expression of CaM protein did not change. Skeletal muscle Ca2+ concentration and the levels of sarcoplasmic reticulum calcium recycling proteins SERCA1 and SERCA2 were increased significantly (P<0.05) in KE mice compared with KO mice, but there were no significant differences in the expressions of the sarcoplasmic reticulum calcium release proteins RyR, CaM and CaMK II. Conclusion: High fat diet can reduce the concentration of Ca2+ in skeletal muscle and weaken the release and recovery of sarcoplasmic reticulum calcium in ApoE knockout mice. 6-week aerobic exercise training can significantly increase its Ca2+concentration and promote the recovery of sarcoplasmic reticulum calcium.


Assuntos
Cálcio , Dieta Hiperlipídica , Animais , Apolipoproteínas E , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Knockout para ApoE , Músculo Esquelético , Retículo Sarcoplasmático
19.
Int J Mol Sci ; 23(16)2022 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-36012328

RESUMO

Cardiac fibrosis is characterized by the net accumulation of extracellular matrix in the myocardium and is an integral component of most pathological cardiac conditions. Cilostazol, a selective inhibitor of phosphodiesterase type III with anti-platelet, anti-mitogenic, and vasodilating properties, is widely used to treat the ischemic symptoms of peripheral vascular disease. Here, we investigated whether cilostazol has a protective effect against Angiotensin II (AngII)-induced cardiac fibrosis. Male apolipoprotein E-deficient mice were fed either a normal diet or a diet containing cilostazol (0.1% wt/wt). After 1 week of diet consumption, the mice were infused with saline or AngII (1000 ng kg-1 min-1) for 28 days. AngII infusion increased heart/body weight ratio (p < 0.05), perivascular fibrosis (p < 0.05), and interstitial cardiac fibrosis (p < 0.0001), but were significantly attenuated by cilostazol treatment (p < 0.05, respectively). Cilostazol also reduced AngII-induced increases in fibrotic and inflammatory gene expression (p < 0.05, respectively). Furthermore, cilostazol attenuated both protein and mRNA abundance of osteopontin induced by AngII in vivo. In cultured human cardiac myocytes, cilostazol reduced mRNA expression of AngII-induced osteopontin in dose-dependent manner. This reduction was mimicked by forskolin treatment but was cancelled by co-treatment of H-89. Cilostazol attenuates AngII-induced cardiac fibrosis in mice through activation of the cAMP-PKA pathway.


Assuntos
Angiotensina II , Cilostazol , Miocárdio , Osteopontina , Angiotensina II/metabolismo , Animais , Cilostazol/farmacologia , Fibrose , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Miocárdio/patologia , RNA Mensageiro
20.
Biomolecules ; 12(8)2022 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-36009040

RESUMO

BACKGROUND: Cardiovascular events are the main cause of death in patients with chronic kidney disease. We hypothesize that the protective effects of renal cholesterol and vitamin D3 metabolism are lost under this condition. Nephropathy was induced by adenine in Apolipoprotein E knockout mice. The atherosclerotic phenotype was compared to mice with normal renal function. METHODS: Mice were fed a western diet ±0.15% adenine. Urine and feces were collected to assess renal function and fecal output. Atherosclerosis, serum lipoprotein composition and functionality, hepatic lipids, and expression of genes involved in lipid metabolism, vitamin D3 and Na+ homeostasis, were assessed. Bones were analyzed by microCT. RESULTS: Mice fed with adenine showed enhanced urinary Na+, Ca2+, and Pi excretion, reduced urinary pH, UreaUrine/UreaSerum, and CreatinineUrine/CreatinineSerum ratios. They developed less atherosclerosis. Lipoproteins in serum and hepatic lipids remained unchanged. Cholesterol efflux increased. Fecal output of cholesteryl ester and triglycerides increased. In the liver, mRNA levels of Cyp27a1, Cyp7a1, and Scarb1 increased; in the kidneys, Slc9a3, Slc12a3, Vdr, and Cyp24a1 decreased. Adenine increased cholesterol efflux in vitro. Tibias were shorter. CONCLUSION: Adenine induced tubular damage and was athero-protective because of enhanced cholesterol efflux and lipids elimination in feces. Bone growth was also affected.


Assuntos
Adenina , Aterosclerose , Adenina/metabolismo , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Colesterol/metabolismo , Creatinina/metabolismo , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Ureia/farmacologia , Vitamina D/farmacologia
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