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1.
Nat Commun ; 11(1): 3984, 2020 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-32770009

RESUMO

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Aterosclerose/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Proteólise , Proteínas Adaptadoras de Transporte Vesicular/química , Animais , Aorta/metabolismo , Aorta/patologia , Aterosclerose/patologia , Cálcio/metabolismo , Colesterol/metabolismo , Células Endoteliais/metabolismo , Feminino , Deleção de Genes , Células HEK293 , Homeostase , Humanos , Inflamação/patologia , Masculino , Camundongos Knockout , Ligação Proteica , Domínios Proteicos , Ubiquitinação
2.
Arterioscler Thromb Vasc Biol ; 40(9): 2095-2107, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32757647

RESUMO

OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of ß-VLDLs-the major atherogenic lipoproteins. ß-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than ß-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.


Assuntos
Doenças da Aorta/prevenção & controle , Apolipoproteína C-III/deficiência , Aterosclerose/prevenção & controle , Doença da Artéria Coronariana/prevenção & controle , Triglicerídeos/sangue , Animais , Animais Geneticamente Modificados , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Apolipoproteína C-III/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/patologia , Modelos Animais de Doenças , Feminino , Células Hep G2 , Hepatócitos/metabolismo , Humanos , Lipoproteínas IDL/sangue , Fígado/metabolismo , Masculino , Oxirredução , Placa Aterosclerótica , Coelhos
3.
Arterioscler Thromb Vasc Biol ; 40(9): 2070-2083, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32762445

RESUMO

OBJECTIVE: Emerging evidence suggests that C3aR (C3a anaphylatoxin receptor) signaling has protective roles in various inflammatory-related diseases. However, its role in atherosclerosis has been unknown. The purpose of the study was to investigate the possible protective role of C3aR in aortic atherosclerosis and explore molecular and cellular mechanisms involved in the protection. Approach and Results: C3ar-/-/Apoe-/- mice were generated by cross-breeding of atherosclerosis-prone Apoe-/- mice and C3ar-/- mice. C3ar-/-/Apoe-/- mice and Apoe-/- mice (as a control) underwent high-fat diet for 16 weeks were assessed for (1) atherosclerotic plaque burden, (2) aortic tissue inflammation, (3) recruitment of CD11b+ leukocytes into atherosclerotic lesions, and (4) systemic inflammatory responses. Compared with Apoe-/- mice, C3ar-/-/Apoe-/- mice developed more severe atherosclerosis. In addition, C3ar-/-/Apoe-/- mice have increased local production of proinflammatory mediators (eg, CCL2 [chemokine (C-C motif) ligand 2], TNF [tumor necrosis factor]-α) and infiltration of monocyte/macrophage in aortic tissue, and their lesional macrophages displayed an M1-like phenotype. Local pathological changes were associated with enhanced systemic inflammatory responses (ie, elevated plasma levels of CCL2 and TNF-α, increased circulating inflammatory cells). In vitro analyses using peritoneal macrophages showed that C3a stimulation resulted in upregulation of M2-associated signaling and molecules, but suppression of M1-associated signaling and molecules, supporting the roles of C3a/C3aR axis in mediating anti-inflammatory response and promoting M2 macrophage polarization. CONCLUSIONS: Our findings demonstrate a protective role for C3aR in the development of atherosclerosis and suggest that C3aR confers the protection through C3a/C3aR axis-mediated negative regulation of proinflammatory responses and modulation of macrophage toward the anti-inflammatory phenotype.


Assuntos
Aorta/metabolismo , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Inflamação/prevenção & controle , Macrófagos Peritoneais/metabolismo , Receptores Acoplados a Proteínas-G/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Doenças da Aorta/imunologia , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/imunologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxia , Modelos Animais de Doenças , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Fenótipo , Placa Aterosclerótica , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Nat Commun ; 11(1): 4084, 2020 08 14.
Artigo em Inglês | MEDLINE | ID: mdl-32796843

RESUMO

Lipid peroxidation generates reactive dicarbonyls including isolevuglandins (IsoLGs) and malondialdehyde (MDA) that covalently modify proteins. Humans with familial hypercholesterolemia (FH) have increased lipoprotein dicarbonyl adducts and dysfunctional HDL. We investigate the impact of the dicarbonyl scavenger, 2-hydroxybenzylamine (2-HOBA) on HDL function and atherosclerosis in Ldlr-/- mice, a model of FH. Compared to hypercholesterolemic Ldlr-/- mice treated with vehicle or 4-HOBA, a nonreactive analogue, 2-HOBA decreases atherosclerosis by 60% in en face aortas, without changing plasma cholesterol. Ldlr-/- mice treated with 2-HOBA have reduced MDA-LDL and MDA-HDL levels, and their HDL display increased capacity to reduce macrophage cholesterol. Importantly, 2-HOBA reduces the MDA- and IsoLG-lysyl content in atherosclerotic aortas versus 4-HOBA. Furthermore, 2-HOBA reduces inflammation and plaque apoptotic cells and promotes efferocytosis and features of stable plaques. Dicarbonyl scavenging with 2-HOBA has multiple atheroprotective effects in a murine FH model, supporting its potential as a therapeutic approach for atherosclerotic cardiovascular disease.


Assuntos
Aterosclerose/metabolismo , Benzilaminas/metabolismo , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Hiperlipoproteinemia Tipo II/metabolismo , Receptores de LDL/genética , Animais , Aorta , Apolipoproteínas E , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Colesterol/metabolismo , Feminino , Humanos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/patologia , Inflamação/tratamento farmacológico , Peroxidação de Lipídeos , Lipoproteínas HDL/metabolismo , Lipoproteínas IDL/sangue , Lipoproteínas IDL/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fragmentos de Peptídeos
5.
Arterioscler Thromb Vasc Biol ; 40(9): 2227-2243, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640901

RESUMO

OBJECTIVE: Perivascular adipose tissue (PVAT) surrounding arteries supports healthy vascular function. During obesity, PVAT loses its vasoprotective effect. We study pathological conversion of PVAT, which involves molecular changes in protein profiles and functional changes in adipocytes. Approach and Results: C57BL6/J mice were fed a 60% high-fat diet for 12 weeks or a cardioprotective 30% calorie-restricted diet for 5 weeks. Proteomic analysis identified PVAT as a molecularly distinct adipose depot, and novel markers for thermogenic adipocytes, such as GRP75 (stress-70 protein, mitochondrial), were identified. High-fat diet increased the similarity of protein signatures in PVAT and brown adipose, suggesting activation of a conserved whitening pathway. The whitening phenotype was characterized by suppression of UCP1 (uncoupling protein 1) and increased lipid deposition, leptin, and inflammation, and specifically in PVAT, elevated Notch signaling. Conversely, PVAT from calorie-restricted mice had decreased Notch signaling and less lipid. Using the Adipoq-Cre strain, we constitutively activated Notch1 signaling in adipocytes, which phenocopied the changes in PVAT caused by a high-fat diet, even on a standard diet. Preadipocytes from mouse PVAT expressed Sca1, CD140a, Notch1, and Notch2, but not CD105, showing differences compared with preadipocytes from other depots. Inhibition of Notch signaling during differentiation of PVAT-derived preadipocytes reduced lipid deposition and adipocyte marker expression. CONCLUSIONS: PVAT shares features with other adipose depots, but has a unique protein signature that is regulated by dietary stress. Increased Notch signaling in PVAT is sufficient to initiate the pathological conversion of PVAT by promoting adipogenesis and lipid accumulation and may thus prime the microenvironment for vascular disease.


Assuntos
Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/metabolismo , Lipogênese , Obesidade/metabolismo , Receptores Notch/metabolismo , Adipócitos Brancos/patologia , Tecido Adiposo Branco/patologia , Adiposidade , Animais , Ataxina-1/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Restrição Calórica , Dieta Hiperlipídica , Modelos Animais de Doenças , Endoglina/metabolismo , Feminino , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/genética , Obesidade/patologia , Fenótipo , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Proteômica , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Notch2/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptores Notch/genética , Transdução de Sinais
6.
Arterioscler Thromb Vasc Biol ; 40(9): 2143-2158, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640903

RESUMO

OBJECTIVE: ERα (estrogen receptor alpha) exerts nuclear genomic actions and also rapid membrane-initiated steroid signaling. The mutation of the cysteine 451 into alanine in vivo has recently revealed the key role of this ERα palmitoylation site on some vasculoprotective actions of 17ß-estradiol (E2) and fertility. Here, we studied the in vivo role of the arginine 260 of ERα which has also been described to be involved in its E2-induced rapid signaling with PI-3K (phosphoinositide 3-kinase) as well as G protein in cultured cell lines. Approach and Results: We generated a mouse model harboring a point mutation of the murine counterpart of this arginine into alanine (R264A-ERα). In contrast to the C451A-ERα, the R264A-ERα females are fertile with standard hormonal serum levels and normal control of hypothalamus-pituitary ovarian axis. Although R264A-ERα protein abundance was normal, the well-described membrane ERα-dependent actions of estradiol, such as the rapid dilation of mesenteric arteries and the acceleration of endothelial repair of carotid, were abrogated in R264A-ERα mice. In striking contrast, E2-regulated gene expression was highly preserved in the uterus and the aorta, revealing intact nuclear/genomic actions in response to E2. Consistently, 2 recognized nuclear ERα-dependent actions of E2, namely atheroma prevention and flow-mediated arterial remodeling were totally preserved. CONCLUSIONS: These data underline the exquisite role of arginine 264 of ERα for endothelial membrane-initiated steroid signaling effects of E2 but not for nuclear/genomic actions. This provides the first model of fertile mouse with no overt endocrine abnormalities with specific loss-of-function of rapid ERα signaling in vascular functions.


Assuntos
Lesões das Artérias Carótidas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Estradiol/farmacologia , Receptor alfa de Estrogênio/agonistas , Terapia de Reposição de Estrogênios , Estrogênios/farmacologia , Fertilidade/efeitos dos fármacos , Artérias Mesentéricas/efeitos dos fármacos , Mutação Puntual , Animais , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Lesões das Artérias Carótidas/metabolismo , Lesões das Artérias Carótidas/patologia , Lesões das Artérias Carótidas/fisiopatologia , Proliferação de Células/efeitos dos fármacos , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Ativação Enzimática , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Ciclo Estral/efeitos dos fármacos , Feminino , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos Endogâmicos C57BL , Óxido Nítrico Sintase Tipo III/metabolismo , Ovariectomia , Reepitelização/efeitos dos fármacos , Transdução de Sinais , Fatores de Tempo , Útero/efeitos dos fármacos , Útero/metabolismo , Remodelação Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
7.
Arterioscler Thromb Vasc Biol ; 40(9): 2108-2113, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32640904

RESUMO

OBJECTIVE: Renin cleavage of angiotensinogen has species specificity. As the residues at positions 11 and 12 are different between human angiotensinogen and mouse angiotensinogen, we determined whether these 2 residues in angiotensinogen affect renin cleavage and angiotensin II-mediated blood pressure regulation and atherosclerosis using an adenoassociated viral approach for manipulating angiotensinogen in vivo. Approach and Results: Hepatocyte-specific angiotensinogen deficient (hepAGT-/-) mice in an LDL receptor-deficient background were infected with adenoassociated virals containing a null insert, human angiotensinogen, or mouse angiotensinogen expressing the same residues of the human protein at positions 11 and 12 (mouse angiotensinogen [L11V;Y12I]). Expression of human angiotensinogen in hepAGT-/- mice led to high plasma human angiotensinogen concentrations without changes in plasma endogenous mouse angiotensinogen, plasma renin concentrations, blood pressure, or atherosclerosis. This is consistent with human angiotensinogen not being cleaved by mouse renin. To determine whether the residues at positions 11 and 12 in human angiotensinogen lead to the inability of mouse renin to cleave human angiotensinogen, hepAGT-/- mice were injected with adenoassociated viral vector encoding mouse angiotensinogen (L11V;Y12I). Expression of mouse angiotensinogen (L11V;Y12I) in hepAGT-/- mice resulted in increased plasma mouse angiotensinogen concentrations, reduced renin concentrations, and increased renal AngII concentrations that were comparable to their concentrations in hepAGT+/+ mice. This mouse angiotensinogen variant increased blood pressure and atherosclerosis in hepAGT-/- mice to the magnitude of hepAGT+/+ mice. CONCLUSIONS: Replacement of L11 and Y12 to V11 and I12, respectively, in mouse angiotensinogen does not affect renin cleavage, blood pressure, and atherosclerosis in LDL receptor-deficient mice.


Assuntos
Angiotensina II/metabolismo , Angiotensinogênio/metabolismo , Aterosclerose/metabolismo , Pressão Sanguínea , Hepatócitos/metabolismo , Hipertensão/metabolismo , Renina/metabolismo , Substituição de Aminoácidos , Angiotensinogênio/deficiência , Angiotensinogênio/genética , Animais , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Humanos , Hipertensão/genética , Hipertensão/fisiopatologia , Masculino , Camundongos Knockout , Placa Aterosclerótica , Receptores de LDL/genética , Receptores de LDL/metabolismo , Especificidade da Espécie
8.
Arterioscler Thromb Vasc Biol ; 40(9): 2002-2017, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698685

RESUMO

Despite major advances in the primary and secondary prevention of atherosclerosis and its risk factors, atherosclerotic cardiovascular disease remains a major clinical and financial burden on individuals and health systems worldwide. In addition, neointima formation and proliferation due to mechanical trauma to the vessel wall during percutaneous coronary interventions can lead to vascular restenosis and limit the longevity and effectiveness of coronary revascularization. Long noncoding RNAs (lncRNAs) have emerged as a novel class of epigenetic regulators with critical roles in the pathogenesis of atherosclerosis and restenosis following vascular injury. Here, we provide an in-depth review of lncRNAs that regulate the development of atherosclerosis or contribute to the pathogenesis of restenosis following mechanical vascular injury. We describe the diverse array of intracellular mechanisms by which lncRNAs exert their regulatory effects. We highlight the utility and challenges of lncRNAs as biomarkers. Finally, we discuss the immense translational potential of lncRNAs and strategies for targeting them therapeutically using oligonucleotide-based therapeutics and novel gene therapy platforms.


Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , RNA Longo não Codificante/metabolismo , Lesões do Sistema Vascular/metabolismo , Animais , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Aterosclerose/terapia , Constrição Patológica , Epigênese Genética , Marcadores Genéticos , Humanos , Oligonucleotídeos Antissenso/uso terapêutico , Placa Aterosclerótica , RNA Longo não Codificante/genética , RNA Longo não Codificante/uso terapêutico , Terapêutica com RNAi , Transdução de Sinais , Remodelação Vascular , Lesões do Sistema Vascular/genética , Lesões do Sistema Vascular/patologia , Lesões do Sistema Vascular/terapia
9.
Arterioscler Thromb Vasc Biol ; 40(9): 2195-2211, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32698686

RESUMO

OBJECTIVE: To delineate temporal and spatial dynamics of vascular smooth muscle cell (SMC) transcriptomic changes during aortic aneurysm development in Marfan syndrome (MFS). Approach and Results: We performed single-cell RNA sequencing to study aortic root/ascending aneurysm tissue from Fbn1C1041G/+ (MFS) mice and healthy controls, identifying all aortic cell types. A distinct cluster of transcriptomically modulated SMCs (modSMCs) was identified in adult Fbn1C1041G/+ mouse aortic aneurysm tissue only. Comparison with atherosclerotic aortic data (ApoE-/- mice) revealed similar patterns of SMC modulation but identified an MFS-specific gene signature, including plasminogen activator inhibitor-1 (Serpine1) and Kruppel-like factor 4 (Klf4). We identified 481 differentially expressed genes between modSMC and SMC subsets; functional annotation highlighted extracellular matrix modulation, collagen synthesis, adhesion, and proliferation. Pseudotime trajectory analysis of Fbn1C1041G/+ SMC/modSMC transcriptomes identified genes activated differentially throughout the course of phenotype modulation. While modSMCs were not present in young Fbn1C1041G/+ mouse aortas despite small aortic aneurysm, multiple early modSMCs marker genes were enriched, suggesting activation of phenotype modulation. modSMCs were not found in nondilated adult Fbn1C1041G/+ descending thoracic aortas. Single-cell RNA sequencing from human MFS aortic root aneurysm tissue confirmed analogous SMC modulation in clinical disease. Enhanced expression of TGF-ß (transforming growth factor beta)-responsive genes correlated with SMC modulation in mouse and human data sets. CONCLUSIONS: Dynamic SMC phenotype modulation promotes extracellular matrix substrate modulation and aortic aneurysm progression in MFS. We characterize the disease-specific signature of modSMCs and provide temporal, transcriptomic context to the current understanding of the role TGF-ß plays in MFS aortopathy. Collectively, single-cell RNA sequencing implicates TGF-ß signaling and Klf4 overexpression as potential upstream drivers of SMC modulation.


Assuntos
Aneurisma Aórtico/genética , Fibrilina-1/genética , Perfilação da Expressão Gênica , Síndrome de Marfan/complicações , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Análise de Célula Única , Transcriptoma , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/genética , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Feminino , Predisposição Genética para Doença , Masculino , Síndrome de Marfan/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Mutação , Miócitos de Músculo Liso/patologia , Fenótipo , RNA-Seq , Fatores de Tempo , Remodelação Vascular/genética
10.
Arch Biochem Biophys ; 690: 108460, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603715

RESUMO

BACKGROUND: Our previous research revealed that trypsin is abundantly expressed in atherosclerotic plaques and its distribution overlaps with that of matrix metalloproteinase-9 (MMP-9). This study was performed to explore the possible roles of trypsin in vulnerable atherosclerotic plaque formation. METHODS AND RESULTS: Twenty-four rabbits were randomly assigned to a normal (control) group, an atherosclerosis (experimental) group and a trypsin inhibitor (aprotinin) group. In the 13th feeding week, the aprotinin group was treated with 5 mg/kg/day aprotinin via ear vein for 4 weeks. At the end of the 16th week, coronary arterial and aortic expression of trypsin, proteinase-activated receptor-2 (PAR-2), activated MMP-9, and pro-inflammatory cytokines were significantly greater in the experimental group than in the control group. Aprotinin decreased trypsin expression and activation in plaques, blocked PAR-2 and MMP-9 activation, and decreased cytokine expression; it also increased fibrous cap thickness, decreased the intima-media thickness and intimal/medial ratio, thus significantly ameliorating plaque vulnerability. Upregulated trypsin, MMP-9 and PAR-2 were also found in coronary intimal atherosclerotic plaques of patients undergoing coronary artery bypass grafting. CONCLUSIONS: Ectopic trypsin was significantly upregulated in atherosclerotic plaques, which increased pro-inflammatory cytokine levels by activating PAR-2 and promoted plaque instability by activating proMMP-9, thereby promoting atherosclerosis and plaque vulnerability. In addition, the high trypsin expression in human coronary intimal atherosclerotic plaques suggests that targeting trypsin may be a new strategy for acute coronary syndrome prevention.


Assuntos
Aterosclerose/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Placa Aterosclerótica/química , Tripsina/metabolismo , Animais , Aorta/química , Aprotinina/administração & dosagem , Aprotinina/metabolismo , Espessura Intima-Media Carotídea , Citocinas/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Coelhos , Receptor PAR-2/metabolismo , Tripsina/genética , Inibidores da Tripsina/administração & dosagem , Inibidores da Tripsina/metabolismo
11.
Life Sci ; 257: 118013, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32603818

RESUMO

AIMS: Emerging literature illustrates critical roles of long noncoding RNAs (lncRNAs) in the progression of atherosclerosis. However, the biological functions and mechanism by which lncRNAs regulate the atherosclerosis remain unclear. MATERIALS AND METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with oxidative low-density lipoprotein (ox-LDL). RNA and protein levels were respectively measured using RT-qPCR and western blot. Molecular interaction was detected using luciferase reporter assay and chromatin immunoprecipitation (ChIP). Proliferation and migration were measured using CCK-8 and wound healing assay. KEY FINDINGS: Here, results unveiled that lncRNA SNHG7 was remarkedly up-regulated in ox-LDL exposed HUVECs. Gain and loss of function experiments showed that the SNHG7 repressed the proliferation and migration of HUVECs. Mechanistically, transcription factor E2F1 was found to target the promoter region of lncRNA SNHG7 and accelerated its expression. Moreover, miR-186-5p was found to bind with the 3'-UTR of SNHG7, meanwhile miR-186-5p also bound with the MMP2 mRNA 3'-UTR. SIGNIFICANCE: In conclusion, these results show the essential roles of E2F1/SNHG7/miR-186-5p/MMP2 axis on the proliferation and migration of endothelial cells, providing a potential therapeutic target for atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Células Endoteliais/metabolismo , RNA Longo não Codificante/metabolismo , Regiões 3' não Traduzidas , Apoptose/genética , Aterosclerose/fisiopatologia , Movimento Celular/genética , Proliferação de Células/genética , Progressão da Doença , Fator de Transcrição E2F1/metabolismo , Células Endoteliais/fisiologia , Técnicas de Silenciamento de Genes , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Lipoproteínas LDL , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Longo não Codificante/genética , RNA Longo não Codificante/fisiologia
12.
Life Sci ; 257: 117658, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32621921

RESUMO

BACKGROUND: Curcumin (Cur) is a hydrophobic polyphenol compound derived from the rhizome of the herb Curcuma longa. Cur has a wide spectrum of biological and pharmacological activities. It has been shown that human cytomegalovirus (HCMV) infection was an important risk factor for atherosclerosis (AS) and Cur exhibited an outstanding anti-HCMV effect. However, anti-AS effects of Cur remain unclear when HCMV infected endothelial cells. AIMS: This study will investigate the anti-AS activities and mechanism of Cur,when HCMV infected in vivo and in vitro. MATERIALS AND METHODS: Cur (0.5, 1, and 2 µM) was used to explore the anti-AS activities and mechanism after HCMV infected endothelial cells in vitro. ApoE-/- mice were fed a high fat and cholesterol diet (HD) and given 4000,000 copies/mouse MCMV infection by intraperitoneal and treated with ganciclovir (5 mg/kg/d), Cur (25, 15 mg/kg/d) for 10 weeks in vivo. KEY FINDINGS: As our results showed that Cur inhibited CMV replication and proliferation, reduced the intracellular ROS overproduction, decreased the release of inflammatory cytokines, down-regulated the level of HMGB1-TLRS-NF-κB signaling pathway-related proteins in vitro experiments. Cur reduced the serum levels of LDL-C, TC and TG, significantly decreased the formation of atherosclerotic plaque in the aorta, reduced the lipid deposition in liver and inflammatory damage in heart, lung and kidney in vivo experiments. SIGNIFICANCE: This study showed that Cur prevent AS progression by inhibiting CMV activity and CMV-induced HMGB1-TLRS-NF-κB signaling pathway.


Assuntos
Aterosclerose/tratamento farmacológico , Curcumina/farmacologia , Citomegalovirus/efeitos dos fármacos , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/metabolismo , Curcuma/metabolismo , Curcumina/metabolismo , Citocinas/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Masculino , Camundongos , Camundongos Transgênicos , NF-kappa B/metabolismo , Extratos Vegetais/farmacologia , Placa Aterosclerótica/metabolismo , Transdução de Sinais/efeitos dos fármacos
13.
Gene ; 755: 144900, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32554046

RESUMO

Atherosclerosis (AS) is a serious threat to the cardiovascular system. Circular RNA circ_0003645 was found to be differentially expressed in the process of AS. Our study tried to unravel the effect and underlying mechanism of circ_0003645 in endothelial cells treated with oxidized low-density lipoprotein (oxLDL). Si-RNAs and over-circ0003645 were transfected into human umbilical vein endothelial cells (HUVECs), and the expression levels of circ_0003645 and NF-κB mRNA were measured. The protein level of NF-κB, lactate dehydrogenase leakage (LDH leakage), cell viability, and apoptosis were detected. Further, the expression of interleukin (IL)-6, tumor necrosis factor (TNF)-α, ICAM-1, and VCAM-1 were measured. Circ_0003645 was found up-regulated in AS patients and in HUVECs treated with oxLDL. The LDH leakage, cell apoptosis, and expression levels of IL-6, TNF-α, ICAM-1, VCAM-1, NF-κB mRNA, NF-κB protein were all inhibited by circ_0003645 silencing, while cell viability was promoted, and the opposite effects were observed by the overexpression of circ_0003645. In conclusion, circ_0003645 silencing alleviated inflammation and apoptosis, while promoted the viability in oxLDL-induced endothelial cells by the NF-κB pathway.


Assuntos
Aterosclerose/genética , Lipoproteínas LDL/farmacologia , NF-kappa B/metabolismo , RNA Circular/genética , Apoptose/fisiologia , Aterosclerose/metabolismo , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Células Endoteliais/metabolismo , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Molécula 1 de Adesão Intercelular/genética , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Interferência de RNA/fisiologia , RNA Circular/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/metabolismo
14.
Cardiovasc Pathol ; 49: 107241, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32554057

RESUMO

In order to accelerate development of atherosclerosis(AS) in miniature swine models, varieties of strategies and methods have been explored. In addition to traditional methods such as high cholesterol feeding and balloon injury, new methods such as familial hypercholesterolemia induced by gene editing and intramural injection have been applied in recent years. Although it has been claimed that these methods have successfully aggravated lesion areas and stenosis, lesion features induced by different strategies have shown heterogeneity in morphology. In addition, time consumption, high cost, and unavailability are problems that restrict application of these AS models. Here, we summarize strategies and methods to accelerate AS models and further analyze their values, advantages, and shortcomings.


Assuntos
Artérias/patologia , Aterosclerose/etiologia , Placa Aterosclerótica , Angioplastia com Balão , Animais , Animais Geneticamente Modificados , Artérias/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica , Modelos Animais de Doenças , Progressão da Doença , Edição de Genes , Predisposição Genética para Doença , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Suínos , Porco Miniatura/genética , Fatores de Tempo
15.
Arch Biochem Biophys ; 689: 108453, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32524996

RESUMO

Nitric oxide (NO) deficiency and NADPH oxidase plays key roles in endothelial dysfunction and atherosclerotic plaque formation. Recent evidence demonstrates that nitrate-nitrite-NO pathway in vivo exerts beneficial effects upon the cardiovascular system. We aimed to investigate the effects of dietary nitrate on endothelial function and atherosclerosis in apolipoprotein E knockout (ApoE-/-) mice fed a high-fat diet. It was shown that dietary nitrate significantly attenuated aortic endothelial dysfunction and atherosclerosis in ApoE-/- mice. Mechanistic studies revealed that dietary nitrate significantly improved plasma nitrate/nitrite, inhibited vascular NADPH oxidase activity and oxidative stress in ApoE-/- mice, while xanthine oxidoreductase (XOR) expression and activity was enhanced in ApoE-/- mice in comparison with wide type animals. These beneficial effects of nitrate in ApoE-/- mice were abolished by PTIO (NO scavenger) and significantly prevented by febuxostat (XOR inhibitor). In the presence of nitrate, no further effect of apocynin (NADPH oxidase inhibitor) was observed, suggesting NADPH oxidase as a possible target. In vitro, NO donor significantly inhibited NADPH oxidase activity in vascular endothelial cells via the induction of heme oxygenase-1. Altogether, boosting this nitrate-nitrite-NO signaling pathway resulted in the decreases of vascular NADPH oxidase-derived oxidative stress and endothelial dysfunction, and consequently protected ApoE-/- mice against atherosclerosis. These findings may have novel nutritional implications for the preventive and therapeutic strategies against vascular endothelial dysfunction in atherosclerotic disease.


Assuntos
Aterosclerose/terapia , Endotélio Vascular/patologia , NADPH Oxidases/metabolismo , Nitratos/uso terapêutico , Animais , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Hiperlipídica/efeitos adversos , Suplementos Nutricionais , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Masculino , Camundongos , Camundongos Knockout , Nitratos/metabolismo , Nitritos/metabolismo , Estresse Oxidativo
16.
Proc Natl Acad Sci U S A ; 117(27): 15818-15826, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541024

RESUMO

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.


Assuntos
Aterosclerose/metabolismo , Clonagem Molecular , Ativação do Complemento , Miócitos de Músculo Liso/metabolismo , Fagocitose/fisiologia , Animais , Antígeno CD47/metabolismo , Linhagem da Célula , Proliferação de Células , Complemento C3/genética , Complemento C3/metabolismo , Feminino , Humanos , Inflamação , Macrófagos/metabolismo , Masculino , Camundongos Knockout para ApoE , Miócitos de Músculo Liso/citologia , Placa Aterosclerótica/metabolismo , Análise de Sequência de RNA , Regulação para Cima
17.
Cardiovasc Ther ; 2020: 6758934, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32565910

RESUMO

Background: Atherosclerosis (AS) is a common severe disease around the world. The merging paper reported that long noncoding RNAs (lncRNAs) took part in diversified pathological processes of AS, although the mechanism remains unknown. This study is aimed at uncovering the profile of lncRNA taurine-upregulated gene 1 (TUG1), which has biological function, and potential mechanism in AS progression in vitro. Methods: Oxidized low-density lipoprotein (ox-LDL) was used for AS model construction in vitro. Levels of lncRNA TUG1, miR-141-3p, and receptor tyrosine kinase-like orphan receptor 2 (ROR2) were detected by quantitative real-time polymerase chain reaction (qRT-PCR) in AS tissues or in ox-LDL-treated vascular smooth muscle cells (HA-VSMCs). The biofunctional effects were examined by 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) and transwell assays. The expression of proliferation-related proteins (CyclinD1, Ki-67) and metastasis-associated proteins (ß-catenin, Vimentin) and ROR2 in cells was determined by western blot analysis. The potential binding sites were predicted by starBase software online and confirmed by dual-luciferase reporter analysis. Results: The expression of TUG1 and ROR2 was promoted in AS tissues and ox-LDL-treated HA-VSMCs. While the low expression of miR-141-3p negatively correlated with that of TUG1 or ROR2 in AS tissues. Silencing of TUG1 inhibited the proliferation, migration, invasion, and metastasis in ox-LDL-treated HA-VSMCs. Moreover, the putative binding sites between miR-141-3p and TUG1 or ROR2 were predicted by starBase software online. Also, miR-141-3p deletion reversed the positive effects of TUG1 knockdown on cells. Besides, downregulation of miR-141-3p disrupted the biofunctional results from ROR2 silencing. Conclusion: TUG1 enhanced the progression of AS in vitro by regulating the miR-141-3p/ROR2 axis.


Assuntos
Aterosclerose/metabolismo , Lipoproteínas LDL/toxicidade , MicroRNAs/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , RNA Longo não Codificante/metabolismo , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/metabolismo , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Regulação da Expressão Gênica , Humanos , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Placa Aterosclerótica , RNA Longo não Codificante/genética , Receptores Órfãos Semelhantes a Receptor Tirosina Quinase/genética , Transdução de Sinais
18.
Vascul Pharmacol ; 131: 106763, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32593718

RESUMO

Atherosclerosis (AS) is one of the most common cardiovascular events in patients with chronic renal insufficiency (CRI). During the development of CRI, uremic toxins, including indoxyl sulfate (IS), are pivotal risk factors for AS. However, the underlying mechanism between AS and IS has not been fully elucidated. The present study was designed to test our hypothesis that IS promotes the AS by regulating viability, proliferation, migration and apoptosis of endothelial cells and vascular smooth muscle cells. In this present study, our date showed that IS inhibited the cell viability of human umbilical vein endothelial cells (HUVECs) and human aortic vascular smooth muscle cells (HA-VSMCs) in a dose-dependent manner (P < .05). Moreover, IS inhibited the proliferation, migration and induced apoptosis of HUVECs and HA-VSMCs significantly (P < .05). However, inhibition of the miR-34a abolished these effects of IS in vitro, indicating that miR-34a is involved in the development of AS induced by IS. In addition, the luciferase reporter gene assay showed that up-regulating of miR-34a inhibited the Notch1 transcriptional activity remarkably (P < .05). The expression of Notch1 decreased after IS treatment, while miR-34a inhibitor attenuated this effect. Moreover, the expression of miR-34a-related proteins Wnt-1, Jag1, E2F1 and SIRT1 decreased, while the expression of p53 increased in HUVECs and HA-VSMCs after IS treatment. Consistently, blockage of miR-34a abolished the remarkable effects on protein expressions induced by IS. Taken together, this study showed that IS can inhibit the proliferation, migration and promote apoptosis of HUVECs and HA-VSMCs through the Notch1 signal and miR-34a-related proteins by up-regulating miR-34a. These findings may provide new insights into the underlying mechanism of AS in CRI.


Assuntos
Apoptose/efeitos dos fármacos , Aterosclerose/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Indicã/toxicidade , MicroRNAs/metabolismo , Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , MicroRNAs/genética , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Receptor Notch1/genética , Receptor Notch1/metabolismo , Transdução de Sinais , Regulação para Cima
19.
Proc Natl Acad Sci U S A ; 117(19): 10476-10483, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32354992

RESUMO

Cholesterol-laden macrophage foam cells are a hallmark of atherosclerosis. For that reason, cholesterol metabolism in macrophages has attracted considerable scrutiny, particularly the mechanisms by which macrophages unload surplus cholesterol (a process referred to as "cholesterol efflux"). Many studies of cholesterol efflux in macrophages have focused on the role of ABC transporters in moving cholesterol onto high-density lipoproteins (HDLs), but other mechanisms for cholesterol efflux likely exist. We hypothesized that macrophages have the capacity to unload cholesterol directly onto adjacent cells. To test this hypothesis, we used methyl-ß-cyclodextrin (MßCD) to load mouse peritoneal macrophages with [13C]cholesterol. We then plated the macrophages (in the absence of serum or HDL) onto smooth muscle cells (SMCs) that had been metabolically labeled with [15N]choline. After incubating the cells overnight in the absence of HDL or serum, we visualized 13C and 15N distribution by nanoscale secondary ion mass spectrometry (NanoSIMS). We observed substantial 13C enrichment in SMCs that were adjacent to [13C]cholesterol-loaded macrophages-including in cytosolic lipid droplets of SMCs. In follow-up studies, we depleted "accessible cholesterol" from the plasma membrane of [13C]cholesterol-loaded macrophages with MßCD before plating the macrophages onto the SMCs. After an overnight incubation, we again observed substantial 13C enrichment in the SMCs adjacent to macrophages. Thus, macrophages transfer cholesterol to adjacent cells in the absence of serum or HDL. We suspect that macrophages within tissues transfer cholesterol to adjacent cells, thereby contributing to the ability to unload surplus cholesterol.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/metabolismo , Colesterol/metabolismo , Macrófagos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/fisiologia , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Transporte Biológico , Células Espumosas/metabolismo , Metabolismo dos Lipídeos , Lipoproteínas HDL/metabolismo , Macrófagos/fisiologia , Macrófagos Peritoneais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Soro/metabolismo , beta-Ciclodextrinas/metabolismo
20.
Nutr Metab Cardiovasc Dis ; 30(6): 889-895, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32409274

RESUMO

AIMS: Kisspeptin-10 (KP-10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention with respect to atherosclerosis, since both KP-10 and GPR54 are expressed at high levels in atheromatous plaques and restenotic lesions after wire-injury. The present review introduces the emerging roles of the KP-10/GPR54 system in atherosclerosis. DATA SYNTHESIS: KP-10 suppresses migration and proliferation of human umbilical vein endothelial cells (HUVECs), and induces senescence in HUVECs. KP-10 increases adhesion of human monocytes to HUVECs. KP-10 also stimulates expression of interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and E-selectin genes in HUVECs. KP-10 enhances oxidized low-density lipoprotein-induced foam cell formation associated with upregulation of CD36 and acyl-coenzyme A: cholesterol acyltransferase-1 in human monocyte-derived macrophages. In human aortic smooth muscle cells, KP-10 suppresses angiotensin II-induced migration and proliferation, however, it enhances apoptosis and activities of matrix metalloproteinase (MMP)-2 and MMP-9 by upregulation of extracellular signal-regulated kinase 1/2, p38, Bax, and caspase-3. Four-week-infusion of KP-10 into Apoe-/- mice accelerates development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation, also, it decreases intraplaque vascular smooth muscle cell content. Proatherosclerotic effects of endogenous and exogenous KP-10 were completely attenuated upon infusion of P234, a GPR54 antagonist, in Apoe-/- mice. CONCLUSION: These findings suggest that KP-10 may contribute to acceleration of progression and to the instability of atheromatous plaques, leading to rupture of plaques. This GPR54 antagonist may be useful for the prevention and treatment of atherosclerosis. Thus, the KP-10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.


Assuntos
Aterosclerose/metabolismo , Vasos Sanguíneos/metabolismo , Kisspeptinas/metabolismo , Placa Aterosclerótica , Receptores de Kisspeptina-1/metabolismo , Animais , Apoptose , Aterosclerose/tratamento farmacológico , Aterosclerose/patologia , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/patologia , Fármacos Cardiovasculares/uso terapêutico , Movimento Celular , Proliferação de Células , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Humanos , Macrófagos/metabolismo , Macrófagos/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Agregação Plaquetária , Receptores de Kisspeptina-1/antagonistas & inibidores , Transdução de Sinais
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