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1.
FASEB J ; 35(10): e21892, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34569651

RESUMO

Atherosclerosis is a chronic inflammatory disorder of the vasculature regulated by cytokines. We have previously shown that extracellular signal-regulated kinase-1/2 (ERK1/2) plays an important role in serine 727 phosphorylation of signal transducer and activator of transcription-1 (STAT1) transactivation domain, which is required for maximal interferon-γ signaling, and the regulation of modified LDL uptake by macrophages in vitro. Unfortunately, the roles of ERK1/2 and STAT1 serine 727 phosphorylation in atherosclerosis are poorly understood and were investigated using ERK1 deficient mice (ERK2 knockout mice die in utero) and STAT1 knock-in mice (serine 727 replaced by alanine; STAT1 S727A). Mouse Atherosclerosis RT² Profiler PCR Array analysis showed that ERK1 deficiency and STAT1 S727A modification produced significant changes in the expression of 18 and 49 genes, respectively, in bone marrow-derived macrophages, with 17 common regulated genes that included those that play key roles in inflammation and cell migration. Indeed, ERK1 deficiency and STAT1 S727A modification attenuated chemokine-driven migration of macrophages with the former also impacting proliferation and the latter phagocytosis. In LDL receptor deficient mice fed a high fat diet, both ERK1 deficiency and STAT1 S727A modification produced significant reduction in plaque lipid content, albeit at different time points. The STAT1 S727A modification additionally caused a significant reduction in plaque content of macrophages and CD3 T cells and diet-induced cardiac hypertrophy index. In addition, there was a significant increase in plasma IL-2 levels and a trend toward increase in plasma IL-5 levels. These studies demonstrate important roles of STAT1 S727 phosphorylation in particular in the regulation of atherosclerosis-associated macrophage processes in vitro together with plaque lipid content and inflammation in vivo, and support further assessment of its therapeutical potential.


Assuntos
Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Receptores de LDL/deficiência , Fator de Transcrição STAT1/metabolismo , Animais , Técnicas de Introdução de Genes , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Fosforilação , Placa Aterosclerótica/genética , Placa Aterosclerótica/patologia , Receptores de LDL/metabolismo , Fator de Transcrição STAT1/genética
2.
Neuron ; 109(15): 2363-2365, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34352209

RESUMO

In this issue of Neuron, Shi et al. (2021) show a protective role for the low-density lipoprotein receptor (LDLR) in tau pathology. Brain overexpression of LDLR lowers apolipoprotein E (apoE), suppresses microglial activation, preserves myelin, and ameliorates neurodegeneration, pointing the way toward potential new therapies.


Assuntos
Doença de Alzheimer , Tauopatias , Doença de Alzheimer/genética , Apolipoproteínas E/genética , Encéfalo/metabolismo , Humanos , Lipoproteínas LDL , Receptores de LDL/genética , Receptores de LDL/metabolismo , Tauopatias/genética
3.
Nutrients ; 13(8)2021 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-34444659

RESUMO

Lipodystrophy syndromes (LD) are a heterogeneous group of very rare congenital or acquired disorders characterized by a generalized or partial lack of adipose tissue. They are strongly associated with severe metabolic dysfunction due to ectopic fat accumulation in the liver and other organs and the dysregulation of several key adipokines, including leptin. Treatment with leptin or its analogues is therefore sufficient to reverse some of the metabolic symptoms of LD in patients and in mouse models through distinct mechanisms. Brown adipose tissue (BAT) thermogenesis has emerged as an important regulator of systemic metabolism in rodents and in humans, but it is poorly understood how leptin impacts BAT in LD. Here, we show in transgenic C57Bl/6 mice overexpressing sterol regulatory element-binding protein 1c in adipose tissue (Tg (aP2-nSREBP1c)), an established model of congenital LD, that daily subcutaneous administration of 3 mg/kg leptin for 6 to 8 weeks increases body temperature without affecting food intake or body weight. This is associated with increased protein expression of the thermogenic molecule uncoupling protein 1 (UCP1) and the sympathetic nerve marker tyrosine hydroxylase (TH) in BAT. These findings suggest that leptin treatment in LD stimulates BAT thermogenesis through sympathetic nerves, which might contribute to some of its metabolic benefits by providing a healthy reservoir for excess circulating nutrients.


Assuntos
Tecido Adiposo Marrom/efeitos dos fármacos , Leptina/farmacologia , Lipodistrofia/tratamento farmacológico , Termogênese , Tecido Adiposo Marrom/inervação , Tecido Adiposo Marrom/metabolismo , Animais , Modelos Animais de Doenças , Lipodistrofia/genética , Lipodistrofia/metabolismo , Lipodistrofia/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/metabolismo , Sistema Nervoso Simpático/fisiopatologia , Tirosina 3-Mono-Oxigenase/metabolismo , Proteína Desacopladora 1/metabolismo
4.
Phytomedicine ; 91: 153688, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34380071

RESUMO

BACKGROUNDS: Atherosclerotic Cardiovascular Disease (ASCVD) is defined as ischemic or endothelial dysfunction-various inflammatory diseases, which is mainly caused by excessive low-density lipoprotein cholesterol (LDL-C) in circulating blood. Gynostemma pentaphyllum is a traditional Chinese medicine, and total Gypenosides are used for the treatment of hyperlipidemia and to reduce circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) level. However, which gypenoside involved in the modulation of PCSK9 expression is still unknown. PURPOSE: This study aimed to discover effective PCSK9 inhibitors from Gypenosides in accordance with the 2019 ESC/EAS guidelines. METHODS: HPLC was employed to determine major six components of Gypenosides. The inhibitory activity on secreted PCSK9 in HepG2 of six major compounds from Gypenosides were screened by ELISA. The level of low-density lipoprotein (LDL) receptor (LDLR) was determined by Flow cytometry and Immunofluorescence. The expression levels of PCSK9, LDLR and Sterol-regulatory element binding proteins-2 (SREBP-2) were analyzed by qPCR and Western blot. DiI-LDL was added to evaluated LDL uptake into HepG2. RESULTS: The results suggested that the mRNA and protein levels of PCSK9 were down-regulated by Gypenoside LVI and the LDLR degradation in lysosomes system was inhibited, thereby leading to an increasing in LDL uptake into HepG2 cells. Furthermore, Gypenoside LVI decreased PCSK9 expression induced by stains. Altogether, Gypenoside LVI enhances LDL uptake into HepG2 cells by increased LDLR level on cell-surface and suppressed PCSK9 expression. CONCLUSION: This indicates that Gypenoside LVI can be used as a useful supplement for statins in the treatment of hypercholesterolemia. This is firstly reported that monomeric compound of G. pentaphyllum planted in Hunan province has the effect of increasing LDL-C uptake in hepatocytes via inhibiting PCSK9 expression.


Assuntos
Gynostemma , Pró-Proteína Convertase 9 , Receptores de LDL/metabolismo , LDL-Colesterol , Gynostemma/química , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Extratos Vegetais/farmacologia , Pró-Proteína Convertase 9/metabolismo
5.
Fish Physiol Biochem ; 47(4): 1299-1311, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34241762

RESUMO

Genistein is an abundant phytoestrogen in soybean. This study aimed to determine the effects of genistein on cholesterol distribution and metabolism in female yellow catfish. Three hundred fish (49.2 ± 1.4 g) were randomly divided into five treatments and received intraperitoneal injections as follows: (1) blank, no injection; (2) control, vehicle only; (3) E2, 17ß-estradiol at 10 µg·g-1 body weight; (4) low genistein doses, genistein at 10 µg·g-1 body weight; (5) high genistein doses, genistein at 100 µg·g-1 body weight. Both high and low genistein doses significantly reduced (p < 0.05) serum TC and LDL-C 24 h after injection. Moreover, the high genistein doses significantly reduced (p < 0.05) serum HDL-C. Both high and low doses of genistein significantly increased (p < 0.05) hepatic TC. Only high genistein doses significantly increased (p < 0.05) ovary TC. In the liver, both high and low genistein doses significantly increased (p < 0.05) protein and mRNA expression of ldlr. Meanwhile, high genistein doses significantly decreased (p < 0.05) mRNA expression of hmgcr. In ovary tissue, high genistein doses significantly decreased (p < 0.05) mRNA expression of cyp11a1. These results suggested that genistein affected the cholesterol distribution in female yellow catfish. Both high and low doses of genistein reduced cholesterol content in blood and increased its content in the liver by increasing the uptake of blood cholesterol. Meanwhile, high genistein doses may inhibit hepatic cholesterol synthesis. Additionally, high genistein doses could increase cholesterol transfer from serum into the ovary and disturb cholesterol conversion to pregnenolone.


Assuntos
Peixes-Gato/metabolismo , Colesterol/metabolismo , Genisteína/farmacologia , Proteínas Quinases Ativadas por AMP/genética , Animais , Peixes-Gato/sangue , Peixes-Gato/genética , Colesterol/sangue , Enzima de Clivagem da Cadeia Lateral do Colesterol/genética , Feminino , Proteínas de Peixes/genética , Proteínas de Peixes/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hidroximetilglutaril-CoA Redutases/genética , Hidroximetilglutaril-CoA Redutases/metabolismo , Injeções Intraperitoneais , Fígado/efeitos dos fármacos , Fígado/metabolismo , Ovário/efeitos dos fármacos , Ovário/metabolismo , Fosfoproteínas/genética , Receptores de LDL/genética , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/genética
6.
Molecules ; 26(12)2021 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-34205604

RESUMO

Rutin (R) and quercetin (Q) are two widespread dietary flavonoids. Previous studies regarding the plasma cholesterol-lowering activity of R and Q generated inconsistent results. The present study was therefore carried out to investigate the effects of R and Q on cholesterol metabolism in both HepG2 cells and hypercholesterolemia hamsters. Results from HepG2 cell experiments demonstrate that both R and Q decreased cholesterol at doses of 5 and 10 µM. R and Q up-regulated both the mRNA and protein expression of sterol regulatory element binding protein 2 (SREBP2), low-density lipoprotein receptor (LDLR), and liver X receptor alpha (LXRα). The immunofluorescence study revealed that R and Q increased the LDLR expression, while only Q improved LDL-C uptake in HepG2 cells. Results from hypercholesterolemia hamsters fed diets containing R (5.5 g/kg diet) and Q (2.5 g/kg diet) for 8 weeks demonstrate that both R and Q had no effect on plasma total cholesterol. In the liver, only Q reduced cholesterol significantly. The discrepancy between the in vitro and in vivo studies was probably due to a poor bioavailability of flavonoids in the intestine. It was therefore concluded that R and Q were effective in reducing cholesterol in HepG2 cells in vitro, whereas in vivo, the oral administration of the two flavonoids had little effect on plasma cholesterol in hamsters.


Assuntos
Colesterol/sangue , Colesterol/metabolismo , Quercetina/farmacologia , Rutina/farmacologia , Administração Oral , Animais , Linhagem Celular Tumoral , Cricetinae , Flavonoides/farmacologia , Células Hep G2 , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipercolesterolemia/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Receptores X do Fígado/metabolismo , Masculino , RNA Mensageiro/metabolismo , Receptores de LDL/sangue , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Regulação para Cima/efeitos dos fármacos
7.
J Biochem Mol Toxicol ; 35(9): e22840, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34227185

RESUMO

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.


Assuntos
Aterosclerose/metabolismo , Diabetes Mellitus/metabolismo , Síndrome Metabólica/metabolismo , Obesidade/metabolismo , Receptor de Insulina/metabolismo , Receptores de LDL/metabolismo , Aterosclerose/história , Diabetes Mellitus/história , História do Século XX , História do Século XXI , Humanos , Insulina/história , Insulina/metabolismo , Síndrome Metabólica/história , Obesidade/história , Receptor de Insulina/história , Receptores de LDL/história , Receptores para Leptina/metabolismo
9.
Folia Histochem Cytobiol ; 59(2): 134-143, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34151999

RESUMO

INTRODUCTION: Vascular smooth muscle cells (VSMCs)-based foam cell formation is a crucial factor in the atherosclerosis process. We aimed to explore the mechanism of Golgi a-mannosidase II (GMII) effects on the VSMCs-based foam cell formation. MATERIAL AND METHODS: VSMCs were exposed to different concentrations of low-density lipoproteins (LDLs), lipopolysaccharide (LPS), and/or GMII inhibitor (swainsonine). The qRT-PCR and western blot were used for expression analysis. Oil Red O staining was used to verify changes of lipid droplets in VSMCs. The translocation of the SCAP from the endoplasmic reticulum (ER) to Golgi was detected by immunofluorescence (IF). RESULTS: LPS disrupted the LDLs-mediated regulation of LDL receptor (LDLr) and increased intracellular cholesterol ester, which was inversely inhibited by swainsonine. The activity of a-mannosidase II and GMII expression were decreased by LDLs but increased by the addition of LPS. Conversely, LPS-induced enhancement was reversed by swainsonine. Additionally, swainsonine reversed the LPS-induced increase of intracellular lipid droplets in the presence of LDLs. Expression analysis demonstrated that LDLr, SCAP, and SREBP2 were up-regulated by LPS, but reversed by swainsonine in LDLs-treated cells. IF staining revealed that swainsonine inhibited the translocation of SCAP to Golgi under inflammatory stress. CONCLUSIONS: Collectively, swainsonine restrained LDLr expression to suppress the formation of VSMCs-based foam cells by reducing SREBP2 and SCAP under inflammatory stress conditions, suggesting that GMII contributes to the formation of VSMCs-based foam cells under inflammatory stress.


Assuntos
Células Espumosas/metabolismo , Inflamação/metabolismo , Manosidases/metabolismo , Músculo Liso Vascular/metabolismo , Ésteres do Colesterol/metabolismo , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/metabolismo , Inibidores Enzimáticos/farmacologia , Complexo de Golgi/efeitos dos fármacos , Complexo de Golgi/metabolismo , Humanos , Inflamação/induzido quimicamente , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lipopolissacarídeos , Manosidases/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Músculo Liso Vascular/citologia , Receptores de LDL/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Swainsonina/farmacologia , Regulação para Cima/efeitos dos fármacos
10.
Cell Prolif ; 54(8): e13083, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34165214

RESUMO

OBJECTIVES: Nodakenin (NK) is a coumarin glucoside that is found in the roots of Angelicae gigas. A limited number of studies have been conducted on the pharmacological activities of NK. Although NK is an important natural resource having anti-inflammatory and antioxidant effects, no investigation has been conducted to examine the effects of NK on obesity and obesity-induced inflammation. MATERIALS AND METHODS: The present study investigated the therapeutic effects of NK treatment on obesity and its complications, and its mechanism of action using differentiated 3T3-L1 adipocytes and high-fat diet (HFD)-induced obese mice. Oil red O staining, western blot assay, qRT-PCR assay, siRNA transfection, enzyme-linked immunosorbent assay, H&E staining, immunohistochemistry, molecular docking and immunofluorescence staining were utilized. RESULTS: Treatment with NK demonstrated anti-adipogenesis effects via the regulation of adipogenic transcription factors and genes associated with triglyceride synthesis in differentiated 3T3-L1 adipocytes. Compared with the control group, the group administered NK showed a suppression in weight gain, dyslipidaemia and the development of fatty liver in HFD-induced obese mice. In addition, NK administration inhibited adipogenic differentiation and obesity-induced inflammation and oxidative stress via the suppression of the VLDLR and MEK/ERK1/2 pathways. This is the first study that has documented the interaction between NK and VLDLR structure. CONCLUSION: These results demonstrate the potential of NK as a natural product-based therapeutic candidate for the treatment of obesity and its complications by targeting adipogenesis and adipose tissue inflammation-associated markers.


Assuntos
Cumarínicos/farmacologia , Glucosídeos/farmacologia , Receptores de LDL/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Diferenciação Celular/efeitos dos fármacos , Colesterol/sangue , Dieta Hiperlipídica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Obesidade/patologia , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Receptores de LDL/antagonistas & inibidores , Receptores de LDL/genética , Ganho de Peso/efeitos dos fármacos
11.
Neuron ; 109(15): 2413-2426.e7, 2021 08 04.
Artigo em Inglês | MEDLINE | ID: mdl-34157306

RESUMO

APOE is the strongest genetic risk factor for late-onset Alzheimer's disease. ApoE exacerbates tau-associated neurodegeneration by driving microglial activation. However, how apoE regulates microglial activation and whether targeting apoE is therapeutically beneficial in tauopathy is unclear. Here, we show that overexpressing an apoE metabolic receptor, LDLR (low-density lipoprotein receptor), in P301S tauopathy mice markedly reduces brain apoE and ameliorates tau pathology and neurodegeneration. LDLR overexpression (OX) in microglia cell-autonomously downregulates microglial Apoe expression and is associated with suppressed microglial activation as in apoE-deficient microglia. ApoE deficiency and LDLR OX strongly drive microglial immunometabolism toward enhanced catabolism over anabolism, whereas LDLR-overexpressing microglia also uniquely upregulate specific ion channels and neurotransmitter receptors upon activation. ApoE-deficient and LDLR-overexpressing mice harbor enlarged pools of oligodendrocyte progenitor cells (OPCs) and show greater preservation of myelin integrity under neurodegenerative conditions. They also show less reactive astrocyte activation in the setting of tauopathy.


Assuntos
Apolipoproteínas E/metabolismo , Degeneração Neural/metabolismo , Receptores de LDL/metabolismo , Tauopatias/metabolismo , Animais , Apolipoproteínas E/genética , Masculino , Camundongos , Camundongos Knockout , Microglia/metabolismo , Tauopatias/genética
12.
J Clin Invest ; 131(14)2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34101620

RESUMO

Inhibitors of microsomal prostaglandin E synthase 1 (mPGES-1) are in the early phase of clinical development. Deletion of mPges-1 in mice confers analgesia, restrains atherogenesis, and fails to accelerate thrombogenesis, while suppressing prostaglandin E2 (PGE2), but increasing the biosynthesis of prostacyclin (PGI2). In low-density lipoprotein receptor-deficient (Ldlr-/-) mice, this last effect represents the dominant mechanism by which mPges-1 deletion restrains thrombogenesis, while suppression of PGE2 accounts for its antiatherogenic effect. However, the effect of mPges-1 depletion on blood pressure (BP) in this setting remains unknown. Here, we show that mPges-1 depletion significantly increased the BP response to salt loading in male Ldlr-/- mice, whereas, despite the direct vasodilator properties of PGI2, deletion of the I prostanoid receptor (Ipr) suppressed this response. Furthermore, combined deletion of the Ipr abrogated the exaggerated BP response in male mPges-1-/- mice. Interestingly, these unexpected BP phenotypes were not observed in female mice fed a high-salt diet (HSD). This is attributable to the protective effect of estrogen in Ldlr-/- mice and in Ipr-/- Ldlr-/- mice. Thus, estrogen compensates for a deficiency in PGI2 to maintain BP homeostasis in response to high salt in hyperlipidemic female mice. In male mice, by contrast, the augmented formation of atrial natriuretic peptide (ANP) plays a similar compensatory role, restraining hypertension and oxidant stress in the setting of Ipr depletion. Hence, men with hyperlipidemia on a HSD might be at risk of a hypertensive response to mPGES-1 inhibitors.


Assuntos
Pressão Sanguínea , Homeostase , Receptores de Epoprostenol/deficiência , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Camundongos Knockout , Prostaglandina-E Sintases/genética , Prostaglandina-E Sintases/metabolismo , Receptores de Epoprostenol/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo
13.
Atherosclerosis ; 328: 23-32, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34077868

RESUMO

BACKGROUND AND AIMS: The thiol transferase glutaredoxin 1 controls redox signaling and cellular functions by regulating the S-glutathionylation status of critical protein thiols. Here we tested the hypothesis that by derepressing the expression of glutaredoxin 1, inhibition of histone deacetylase 2 prevents nutrient stress-induced protein S-glutathionylation and monocyte dysfunction and protects against atherosclerosis. METHODS: Using both a pharmacological inhibitor and shRNA-mediated knockdown of histone deacetylase 2, we determine the role of this deacetylase on glutaredoxin 1 expression and nutrient stress-induced inactivation of mitogen-activated protein kinase phosphatase 1 activity and monocyte and macrophage dysfunction. To assess whether histone deacetylase 2 inhibition in myeloid cells protects against atherosclerosis, we fed eight-week-old female and male HDAC2-/-MyeloidLDLR-/- mice and age and sex-matched LysMcretg/wtLDLR-/- control mice a high-calorie diet for 12 weeks and assessed monocyte function and atherosclerotic lesion size. RESULTS: Myeloid histone deacetylase 2 deficiency in high-calorie diet-fed LDLR-/- mice reduced atherosclerosis in males by 39% without affecting plasma lipid and lipoprotein profiles or blood glucose levels but had no effect on atherogenesis in female mice. Macrophage content in plaques of male mice was reduced by 31%. Histone deacetylase 2-deficient blood monocytes from male mice showed increased acetylation on histone 3, and increased Grx1 expression, and was associated with increased MKP-1 activity and reduced recruitment of monocyte-derived macrophages, whereas in females, myeloid HDAC2 deficiency had no effect on Grx1 expression, did not prevent nutrient stress-induced loss of MKP-1 activity in monocytes and was not atheroprotective. CONCLUSIONS: Specific histone deacetylase 2 inhibitors may represent a potential novel therapeutic strategy for the prevention and treatment of atherosclerosis, but any benefits may be sexually dimorphic.


Assuntos
Aterosclerose , Monócitos , Animais , Aterosclerose/prevenção & controle , Dieta , Feminino , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Histona Desacetilase 2/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/metabolismo , Oxirredução , Receptores de LDL/genética , Receptores de LDL/metabolismo , Compostos de Sulfidrila
14.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070931

RESUMO

It is now about 20 years since the first case of a gain-of-function mutation involving the as-yet-unknown actor in cholesterol homeostasis, proprotein convertase subtilisin/kexin type 9 (PCSK9), was described. It was soon clear that this protein would have been of huge scientific and clinical value as a therapeutic strategy for dyslipidemia and atherosclerosis-associated cardiovascular disease (CVD) management. Indeed, PCSK9 is a serine protease belonging to the proprotein convertase family, mainly produced by the liver, and essential for metabolism of LDL particles by inhibiting LDL receptor (LDLR) recirculation to the cell surface with the consequent upregulation of LDLR-dependent LDL-C levels. Beyond its effects on LDL metabolism, several studies revealed the existence of additional roles of PCSK9 in different stages of atherosclerosis, also for its ability to target other members of the LDLR family. PCSK9 from plasma and vascular cells can contribute to the development of atherosclerotic plaque and thrombosis by promoting platelet activation, leukocyte recruitment and clot formation, also through mechanisms not related to systemic lipid changes. These results further supported the value for the potential cardiovascular benefits of therapies based on PCSK9 inhibition. Actually, the passive immunization with anti-PCSK9 antibodies, evolocumab and alirocumab, is shown to be effective in dramatically reducing the LDL-C levels and attenuating CVD. While monoclonal antibodies sequester circulating PCSK9, inclisiran, a small interfering RNA, is a new drug that inhibits PCSK9 synthesis with the important advantage, compared with PCSK9 mAbs, to preserve its pharmacodynamic effects when administrated every 6 months. Here, we will focus on the major understandings related to PCSK9, from its discovery to its role in lipoprotein metabolism, involvement in atherothrombosis and a brief excursus on approved current therapies used to inhibit its action.


Assuntos
Aterosclerose/genética , LDL-Colesterol/metabolismo , Dislipidemias/genética , Placa Aterosclerótica/genética , Pró-Proteína Convertase 9/genética , Trombose/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/enzimologia , Aterosclerose/patologia , Plaquetas/efeitos dos fármacos , Plaquetas/enzimologia , Plaquetas/patologia , LDL-Colesterol/antagonistas & inibidores , Dislipidemias/tratamento farmacológico , Dislipidemias/enzimologia , Dislipidemias/patologia , Fibrinolíticos/uso terapêutico , Regulação da Expressão Gênica , Humanos , Hipolipemiantes/uso terapêutico , Metabolismo dos Lipídeos/efeitos dos fármacos , Metabolismo dos Lipídeos/genética , Placa Aterosclerótica/tratamento farmacológico , Placa Aterosclerótica/enzimologia , Placa Aterosclerótica/patologia , Ativação Plaquetária/efeitos dos fármacos , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/biossíntese , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/genética , Receptores de LDL/metabolismo , Transdução de Sinais , Trombose/enzimologia , Trombose/patologia , Trombose/prevenção & controle
15.
Biomed Pharmacother ; 140: 111758, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058443

RESUMO

BACKGROUND: Cancer is emerging as a major problem globally, as it accounts for the second cause of death despite medical advances. According to epidemiological and basic studies, cholesterol is involved in cancer progression and there are abnormalities in cholesterol metabolism of cancer cells including prostate, breast, and colorectal carcinomas. However, the importance of cholesterol in carcinogenesis and thereby the role of cholesterol homeostasis as a therapeutic target is still a debated area in cancer therapy. Proprotein convertase subtilisin/kexin type-9 (PCSK9), a serine protease, modulates cholesterol metabolism by attachment to the LDL receptor (LDLR) and reducing its recycling by targeting the receptor for lysosomal destruction. Published research has shown that PCSK9 is also involved in degradation of other LDLR family members namely very-low-density-lipoprotein receptor (VLDLR), lipoprotein receptor-related protein 1 (LRP-1), and apolipoprotein E receptor 2 (ApoER2). As a result, this protein represents an interesting therapeutic target for the treatment of hypercholesterolemia. Interestingly, clinical trials on PCSK9-specific monoclonal antibodies have reported promising results with high efficacy in lowering LDL-C and in turn reducing cardiovascular complications. It is important to note that PCSK9 mediates several other pathways apart from its role in lipid homeostasis, including antiviral activity, hepatic regeneration, neuronal apoptosis, and modulation of various signaling pathways. Furthermore, recent literature has illustrated that PCSK9 is closely associated with incidence and progression of several cancers. In a number of studies, PCSK9 siRNA was shown to effectively suppress the proliferation and invasion of the several studied tumor cells. Hence, a novel application of PCSK9 inhibitors/silencers in cancer/metastasis could be considered. However, due to poor data on effectiveness and safety of PCSK9 inhibitors in cancer, the impact of PCSK9 inhibition in these pathological conditions is still unknown. SEARCH METHODS: A vast literature search was conducted to find intended studies from 1956 up to 2020, and inclusion criteria were original peer-reviewed publications. PURPOSE OF REVIEW: To date, PCSK9 has been scantly investigated in cancer. The question that needs to be discussed is "How does PCSK9 act in cancer pathophysiology and what are the risks or benefits associated to its inhibition?". We reviewed the available publications highlighting the contribution of this proprotein convertase in pathways related to cancer, with focus on the potential implications of its long-term pharmacological inhibition in cancer therapy.


Assuntos
Neoplasias/metabolismo , Pró-Proteína Convertase 9/metabolismo , Animais , Carcinogênese/metabolismo , Humanos , Neoplasias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Receptores de LDL/metabolismo
16.
J Biol Chem ; 297(1): 100842, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34058195

RESUMO

The low-density lipoprotein receptor (LDLR) family of receptors are cell-surface receptors that internalize numerous ligands and play crucial role in various processes, such as lipoprotein metabolism, hemostasis, fetal development, etc. Previously, receptor-associated protein (RAP) was described as a molecular chaperone for LDLR-related protein 1 (LRP1), a prominent member of the LDLR family. We aimed to verify this role of RAP for LRP1 and two other LDLR family receptors, LDLR and vLDLR, and to investigate the mechanisms of respective interactions using a cell culture model system, purified system, and in silico modelling. Upon coexpression of RAP with clusters of the ligand-binding complement repeats (CRs) of the receptors in secreted form in insect cells culture, the isolated proteins had increased yield, enhanced folding, and improved binding properties compared with proteins expressed without RAP, as determined by circular dichroism and surface plasmon resonance. Within LRP1 CR-clusters II and IV, we identified multiple sites comprised of adjacent CR doublets, which provide alternative bivalent binding combinations with specific pairs of lysines on RAP. Mutational analysis of these lysines within each of isolated RAP D1/D2 and D3 domains having high affinity to LRP1 and of conserved tryptophans on selected CR-doublets of LRP1, as well as in silico docking of a model LRP1 CR-triplet with RAP, indicated a universal role for these residues in interaction of RAP and LRP1. Consequently, we propose a new model of RAP interaction with LDLR family receptors based on switching of the bivalent contacts between molecules over time in a dynamic mode.


Assuntos
Proteína Associada a Proteínas Relacionadas a Receptor de LDL/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/metabolismo , Dobramento de Proteína , Receptores de LDL/metabolismo , Análise Mutacional de DNA , Humanos , Ligantes , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade/química , Simulação de Acoplamento Molecular , Ligação Proteica , Sequências Repetitivas de Aminoácidos
18.
Arterioscler Thromb Vasc Biol ; 41(6): e338-e353, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33792343
20.
Biochem Biophys Res Commun ; 556: 192-198, 2021 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-33845309

RESUMO

Helicobacter pylori (H. pylori) infection mainly causes gastroduodenal diseases, including chronic gastritis, peptic ulcer disease and gastric cancer. In recent years, several studies have demonstrated that infection with H. pylori, especially strains harboring the virulence factor CagA (cytotoxin-associated gene A), contribute to the development of non-gastric systemic diseases, including hypercholesterolemia and atherosclerotic cardiovascular diseases. However, mechanisms underlying this association has not been defined. In this study, we carried out a large-scale genetic screen using Drosophila and identified a novel CagA target low-density lipoprotein receptor (LDLR), which aids in the clearance of circulating LDL. We showed that CagA physically interacted with LDLR via its carboxy-terminal region and inhibited LDLR-mediated LDL uptake into cells. Since deficiency of LDLR-mediated LDL uptake has been known to increase plasma LDL and accelerate atherosclerosis, our findings may provide a novel mechanism for the association between infection with CagA-positive H. pylori and hypercholesterolemia leading to atherosclerotic cardiovascular diseases.


Assuntos
Antígenos de Bactérias/metabolismo , Proteínas de Bactérias/metabolismo , Helicobacter pylori/metabolismo , Helicobacter pylori/patogenicidade , Lipoproteínas LDL/metabolismo , Receptores de LDL/metabolismo , Fatores de Virulência/metabolismo , Animais , Animais Geneticamente Modificados , Aterosclerose/microbiologia , Drosophila melanogaster/anatomia & histologia , Drosophila melanogaster/genética , Drosophila melanogaster/metabolismo , Olho/metabolismo , Feminino , Humanos , Hipercolesterolemia/microbiologia , Lipoproteínas LDL/sangue , Masculino , Ligação Proteica
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