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1.
Circ Res ; 133(3): 200-219, 2023 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-37350264

RESUMO

BACKGROUND: The mTOR (mechanistic target of rapamycin) pathway is a complex signaling cascade that regulates cellular growth, proliferation, metabolism, and survival. Although activation of mTOR signaling has been linked to atherosclerosis, its direct role in lesion progression and in plaque macrophages remains poorly understood. We previously demonstrated that mTORC1 (mTOR complex 1) activation promotes atherogenesis through inhibition of autophagy and increased apoptosis in macrophages. METHODS: Using macrophage-specific Rictor- and mTOR-deficient mice, we now dissect the distinct functions of mTORC2 pathways in atherogenesis. RESULTS: In contrast to the atheroprotective effect seen with blockade of macrophage mTORC1, macrophage-specific mTORC2-deficient mice exhibit an atherogenic phenotype, with larger, more complex lesions and increased cell death. In cultured macrophages, we show that mTORC2 signaling inhibits the FoxO1 (forkhead box protein O1) transcription factor, leading to suppression of proinflammatory pathways, especially the inflammasome/IL (interleukin)-1ß response, a key mediator of vascular inflammation and atherosclerosis. In addition, administration of FoxO1 inhibitors efficiently rescued the proinflammatory response caused by mTORC2 deficiency both in vitro and in vivo. Interestingly, collective deletion of macrophage mTOR, which ablates mTORC1- and mTORC2-dependent pathways, leads to minimal change in plaque size or complexity, reflecting the balanced yet opposing roles of these signaling arms. CONCLUSIONS: Our data provide the first mechanistic details of macrophage mTOR signaling in atherosclerosis and suggest that therapeutic measures aimed at modulating mTOR need to account for its dichotomous functions.


Assuntos
Aterosclerose , Serina-Treonina Quinases TOR , Camundongos , Animais , Alvo Mecanístico do Complexo 2 de Rapamicina , Serina-Treonina Quinases TOR/metabolismo , Macrófagos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Fatores de Transcrição/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo
2.
Proc Natl Acad Sci U S A ; 118(48)2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34815341

RESUMO

We studied the brain mechanisms underlying action selection in a social dilemma setting in which individuals' effortful gains are unfairly distributed among group members. A stable "worker-parasite" relationship developed when three individually operant-conditioned rats were placed together in a Skinner box equipped with response lever and food dispenser on opposite sides. Specifically, one rat, the "worker," engaged in lever-pressing while the other two "parasitic" rats profited from the worker's effort by crowding the feeder in anticipation of food. Anatomically, c-Fos expression in the anterior cingulate cortex (ACC) was significantly higher in worker rats than in parasite rats. Functionally, ACC inactivation suppressed the worker's lever-press behavior drastically under social, but only mildly under individual, settings. Transcriptionally, GABAA receptor- and potassium channel-related messenger RNA expressions were reliably lower in the worker's, relative to parasite's, ACC. These findings indicate the requirement of ACC activation for the expression of exploitable, effortful behavior, which could be mediated by molecular pathways involving GABAA receptor/potassium channel proteins.


Assuntos
Comportamento de Escolha/fisiologia , Condicionamento Operante/fisiologia , Giro do Cíngulo/patologia , Tonsila do Cerebelo/metabolismo , Animais , Comportamento Animal , Tomada de Decisões/fisiologia , Masculino , Canais de Potássio/metabolismo , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley , Recompensa , Comportamento Social
3.
Allergy ; 77(7): 2131-2146, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35038351

RESUMO

BACKGROUND: NLRP3-driven inflammatory responses by circulating and lung-resident monocytes are critical drivers of asthma pathogenesis. Autophagy restrains NLRP3-induced monocyte activation in asthma models. Yet, the effects of autophagy and its master regulator, transcription factor EB (TFEB), on monocyte responses in human asthma remain unexplored. Here, we investigated whether activation of autophagy and TFEB signaling suppress inflammatory monocyte responses in asthmatic individuals. METHODS: Peripheral blood CD14+ monocytes from asthmatic patients (n = 83) and healthy controls (n = 46) were stimulated with LPS/ATP to induce NLRP3 activation with or without the autophagy inducer, rapamycin. ASC specks, caspase-1 activation, IL-1ß and IL-18 levels, mitochondrial function, ROS release, and mTORC1 signaling were examined. Autophagy was evaluated by LC3 puncta formation, p62/SQSTM1 degradation and TFEB activation. In a severe asthma (SA) model, we investigated the role of NLRP3 signaling using Nlrp3-/- mice and/or MCC950 administration, and the effects of TFEB activation using myeloid-specific TFEB-overexpressing mice or administration of the TFEB activator, trehalose. RESULTS: We observed increased NLRP3 inflammasome activation, concomitant with impaired autophagy in circulating monocytes that correlated with asthma severity. SA patients also exhibited mitochondrial dysfunction and ROS accumulation. Autophagy failed to inhibit NLRP3-driven monocyte responses, due to defective TFEB activation and excessive mTORC1 signaling. NLRP3 blockade restrained inflammatory cytokine release and linked airway disease. TFEB activation restored impaired autophagy, attenuated NLRP3-driven pulmonary inflammation, and ameliorated SA phenotype. CONCLUSIONS: Our studies uncover a crucial role for TFEB-mediated reprogramming of monocyte inflammatory responses, raising the prospect that this pathway can be therapeutically harnessed for the management of SA.


Assuntos
Asma , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Asma/metabolismo , Autofagia , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/metabolismo , Inflamassomos/metabolismo , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Espécies Reativas de Oxigênio/metabolismo
4.
Circulation ; 142(18): 1736-1751, 2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883094

RESUMO

BACKGROUND: Macrophages produce many inflammation-associated molecules, released by matrix metalloproteinases, such as adhesion molecules, and cytokines, as well, which play a crucial role in atherosclerosis. In this context, we investigated the relationship between Ninjurin-1 (Ninj1 [nerve injury-induced protein]), a novel matrix metalloproteinase 9 substrate, expression, and atherosclerosis progression. METHODS: Ninj1 expression and atherosclerosis progression were assessed in atherosclerotic aortic tissue and serum samples from patients with coronary artery disease and healthy controls, and atheroprone apolipoprotein e-deficient (Apoe-/-) and wild-type mice, as well. Apoe-/- mice lacking systemic Ninj1 expression (Ninj1-/-Apoe-/-) were generated to assess the functional effects of Ninj1. Bone marrow transplantation was also used to generate low-density lipoprotein receptor-deficient (Ldlr-/-) mice that lack Ninj1 specifically in bone marrow-derived cells. Mice were fed a Western diet for 5 to 23 weeks, and atherosclerotic lesions were investigated. The anti-inflammatory role of Ninj1 was verified by treating macrophages and mice with the peptides Ninj11-56 (ML56) and Ninj126-37 (PN12), which mimic the soluble form of Ninj1 (sNinj1). RESULTS: Our in vivo results conclusively showed a correlation between Ninj1 expression in aortic macrophages and the extent of human and mouse atherosclerotic lesions. Ninj1-deficient macrophages promoted proinflammatory gene expression by activating mitogen-activated protein kinase and inhibiting the phosphoinositide 3-kinase/Akt signaling pathway. Whole-body and bone marrow-specific Ninj1 deficiencies significantly increased monocyte recruitment and macrophage accumulation in atherosclerotic lesions through elevated macrophage-mediated inflammation. Macrophage Ninj1 was directly cleaved by matrix metalloproteinase 9 to generate a soluble form that exhibited antiatherosclerotic effects, as assessed in vitro and in vivo. Treatment with the sNinj1-mimetic peptides, ML56 and PN12, reduced proinflammatory gene expression in human and mouse classically activated macrophages, thereby attenuating monocyte transendothelial migration. Moreover, continuous administration of mPN12 alleviated atherosclerosis by inhibiting the enhanced monocyte recruitment and inflammation characteristics of this disorder in mice, regardless of the presence of Ninj1. CONCLUSIONS: Ninj1 is a novel matrix metalloproteinase 9 substrate in macrophages, and sNinj1 is a secreted atheroprotective protein that regulates macrophage inflammation and monocyte recruitment in atherosclerosis. Moreover, sNinj1-mediated anti-inflammatory effects are conserved in human macrophages and likely contribute to human atherosclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Aterosclerose , Moléculas de Adesão Celular Neuronais , Macrófagos/metabolismo , Fatores de Crescimento Neural , Peptidomiméticos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Moléculas de Adesão Celular Neuronais/farmacologia , Feminino , Masculino , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Knockout para ApoE , Fatores de Crescimento Neural/genética , Fatores de Crescimento Neural/metabolismo , Fatores de Crescimento Neural/farmacologia , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética
5.
J Immunol ; 201(6): 1784-1798, 2018 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-30097529

RESUMO

Ischemic myocardial injury results in sterile cardiac inflammation that leads to tissue repair, two processes controlled by mononuclear phagocytes. Despite global burden of cardiovascular diseases, we do not understand the functional contribution to pathogenesis of specific cardiac mononuclear phagocyte lineages, in particular dendritic cells. To address this limitation, we used detailed lineage tracing and genetic studies to identify bona fide murine and human CD103+ conventional dendritic cell (cDC)1s, CD11b+ cDC2s, and plasmacytoid DCs (pDCs) in the heart of normal mice and immunocompromised NSG mice reconstituted with human CD34+ cells, respectively. After myocardial infarction (MI), the specific depletion of cDCs, but not pDCs, improved cardiac function and prevented adverse cardiac remodeling. Our results showed that fractional shortening measured after MI was not influenced by the absence of pDCs. Interestingly, however, depletion of cDCs significantly improved reduction in fractional shortening. Moreover, fibrosis and cell areas were reduced in infarcted zones. This correlated with reduced numbers of cardiac macrophages, neutrophils, and T cells, indicating a blunted inflammatory response. Accordingly, mRNA levels of proinflammatory cytokines IL-1ß and IFN-γ were reduced. Collectively, our results demonstrate the unequivocal pathological role of cDCs following MI.


Assuntos
Movimento Celular/imunologia , Células Dendríticas/imunologia , Infarto do Miocárdio/imunologia , Animais , Movimento Celular/genética , Células Dendríticas/patologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Camundongos Knockout , Monócitos/imunologia , Monócitos/patologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Neutrófilos/imunologia , Neutrófilos/patologia , Linfócitos T/imunologia , Linfócitos T/patologia
6.
Curr Opin Lipidol ; 29(3): 203-211, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29601311

RESUMO

PURPOSE OF REVIEW: Intracellular lipid metabolism is a complex interplay of exogenous lipid handling, trafficking, storage, lipolysis, and export. Recent work has implicated the cellular degradative process called autophagy in several aspects of lipid metabolism. We will discuss both the classical and novel roles of autophagy and the autophagic machinery in this setting. RECENT FINDINGS: The delivery of lipid droplets to lysosomes for hydrolysis, named lipophagy, was the first described functional role for autophagy in lipid metabolism. The molecular machinery and regulation of this selective form of macroautophagy is beginning to be discovered and has the potential to shed enormous light on intracellular lipolysis. Yet, the autophagic machinery appears to also be coopted for alternative roles that include interaction with cytosolic lipolysis pathways, supply and expansion of lipid droplets, and lipoprotein trafficking. Additionally, lesser studied forms of autophagy called microautophagy and chaperone-mediated autophagy have distinct roles in lipid handling that also intersect with classical macroautophagy. The integration of current knowledge in these areas into a holistic understanding of intracellular lipid metabolism will be a goal of this review. SUMMARY: As the field of autophagy has evolved and expanded to include functional roles in various aspects of cellular degradation, so has its role in intracellular lipid metabolism. Understanding the mechanisms underlying these classical and alternative roles of autophagy will not only enhance our knowledge in lipid biology but also provide new avenues of translation to human lipid disorders.


Assuntos
Autofagia , Gotículas Lipídicas/metabolismo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipólise , Lipoproteínas/metabolismo , Lisossomos/metabolismo , Animais , Humanos , Gotículas Lipídicas/patologia , Transtornos do Metabolismo dos Lipídeos/patologia , Lisossomos/patologia , Transporte Proteico
7.
FASEB J ; 28(11): 4779-91, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25059229

RESUMO

CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in atherosclerotic plaques, and to promote lesion formation. However, the role of CD137 in mediating atherosclerotic plaque stability and the possible underlying molecular and cellular mechanisms are poorly understood. Here, apolipoprotein E-deficient (ApoE(-/-)) and CD137-deficient ApoE(-/-) (ApoE(-/-)CD137(-/-)) mice fed a chow diet for 66 wk were used. CD137 induces plaque instability, which is characterized by increased plaque necrosis, decreased collagen content, decreased vascular smooth muscle cell (VSMC) content, and increased macrophage infiltration. CD137 also increases the infiltration of effector T (Teff) cells into plaque lesion sites, resulting in increased interferon-γ (IFN-γ) expression. Interestingly, Teff-cell-derived IFN-γ inhibits collagen synthesis in atherosclerotic plaques. Furthermore, CD137 activation increases the apoptosis of VSMCs, possibly by decreasing the antiapoptotic regulator, Bcl-2, and subsequently up-regulating cleaved caspase-3. In macrophages, activation of CD137 signaling boosted the oxidized low density lipoprotein-induced expression of matrix metalloproteinase 9 via the p38 mitogen-activated protein kinase and extracellular signal-regulated kinase1/2 signaling pathways. In summary, activation of CD137 signaling decreases the stability of advanced atherosclerotic plaques via its combined effects on Teff cells, VSMCs, and macrophages.


Assuntos
Ligante 4-1BB/imunologia , Aterosclerose/metabolismo , Hiperlipidemias/metabolismo , Macrófagos/metabolismo , Placa Aterosclerótica/metabolismo , Linfócitos T/metabolismo , Animais , Apoptose/efeitos dos fármacos , Aterosclerose/imunologia , Interferon gama/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica/imunologia , Transdução de Sinais/imunologia , Linfócitos T/imunologia
8.
Zoolog Sci ; 31(11): 748-57, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25366158

RESUMO

Parvalbumin (PV) is thought to play a major role in buffering intracellular calcium. We studied the distribution, morphology of PV-immunoreactive (IR) cells, and the effect of enucleation on the PV distribution in the superior colliculus (SC) in dog (Canis familiaris) and compared PV labeling to that of calbindin D28K (CB) and GABA. These cells formed three laminar tiers in the dog SC; 1) the upper superficial gray layer (SGL), 2) the lower optic layer (OL) and the upper intermediate gray layer, and 3) the deep layer. The third tier was not very distinct when compared with the other two tiers. The distribution of PV-IR cells is thus complementary to that of CB-IR tiers. Our present data on the distribution of PV-IR cells within the superficial layers are strikingly different from those in previously studied mammals, which show PV-IR cells within the lower SGL and upper OL. However, there were no distinct differences in distribution within the deep layers compared with that of previously studied mammals. PV-IR cells in the SC varied dramatically in morphology and size, and included round/oval, vertical fusiform, stellate, horizontal and pyriform cells. Two-color immunofluorescence revealed quantitatively that 11.67% of the PV-IR cells colocalized with GABA. Monocular enucleation appeared to have no effect on the distribution of PV-IR cells in the contralateral SC. Similar to CB, these data suggest that retinal projection may not control the expression of PV in the dog SC. These results provide important information for delineating similarities and differences in the neurochemical architecture of the visual system.


Assuntos
Cães/fisiologia , Enucleação Ocular/veterinária , Parvalbuminas/metabolismo , Colículos Superiores/citologia , Ácido gama-Aminobutírico/metabolismo , Animais , Neurônios/metabolismo , Neurônios/ultraestrutura , Colículos Superiores/fisiologia
9.
Osong Public Health Res Perspect ; 15(2): 137-149, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38621766

RESUMO

BACKGROUND: This study was conducted to assess the efficacy of nirmatrelvir/ritonavir treatment in patients with coronavirus disease 2019 (COVID-19), particularly those aged 60 years and older. Using real-world data, the period during which the BN.1 Omicron variant was dominant was compared to the period dominated by the BA.5 variant. METHODS: In this retrospective cohort study, data were collected regarding 2,665,281 patients infected with severe acute respiratory syndrome coronavirus 2 between July 24, 2022, and March 31, 2023. Propensity score matching was utilized to match patients who received nirmatrelvir/ ritonavir in a 1:4 ratio between BN.1 and BA.5 variant groups. Multivariable logistic regression analysis was employed to assess the effects of nirmatrelvir/ritonavir within these groups. RESULTS: Compared to the prior period, the efficacy of nirmatrelvir/ritonavir did not significantly differ during the interval of Omicron BN.1 variant dominance in the Republic of Korea. Among patients treated with nirmatrelvir/ritonavir, a significantly lower risk of mortality was observed in the BN.1 group (odds ratio [OR], 0.698; 95% confidence interval [CI], 0.557-0.875) compared to the BA.5 group. However, this treatment did not significantly reduce the risk of severe or critical illness, including death, for those in the BN.1 group (OR, 0.856; 95% CI, 0.728-1.007). CONCLUSION: Nirmatrelvir/ritonavir has maintained its effectiveness against COVID-19, even with the emergence of the BN.1 Omicron subvariant. Consequently, we strongly recommend the administration of nirmatrelvir/ritonavir to patients exhibiting COVID-19-related symptoms, irrespective of the dominant Omicron variant or their vaccination status, to mitigate disease severity and decrease the risk of mortality.

10.
Nat Metab ; 6(2): 359-377, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38409323

RESUMO

High protein intake is common in western societies and is often promoted as part of a healthy lifestyle; however, amino-acid-mediated mammalian target of rapamycin (mTOR) signalling in macrophages has been implicated in the pathogenesis of ischaemic cardiovascular disease. In a series of clinical studies on male and female participants ( NCT03946774 and NCT03994367 ) that involved graded amounts of protein ingestion together with detailed plasma amino acid analysis and human monocyte/macrophage experiments, we identify leucine as the key activator of mTOR signalling in macrophages. We describe a threshold effect of high protein intake and circulating leucine on monocytes/macrophages wherein only protein in excess of ∼25 g per meal induces mTOR activation and functional effects. By designing specific diets modified in protein and leucine content representative of the intake in the general population, we confirm this threshold effect in mouse models and find ingestion of protein in excess of ∼22% of dietary energy requirements drives atherosclerosis in male mice. These data demonstrate a mechanistic basis for the adverse impact of excessive dietary protein on cardiovascular risk.


Assuntos
Doenças Cardiovasculares , Humanos , Masculino , Feminino , Camundongos , Animais , Leucina/metabolismo , Leucina/farmacologia , Fatores de Risco , Serina-Treonina Quinases TOR/metabolismo , Macrófagos/metabolismo , Fatores de Risco de Doenças Cardíacas , Mamíferos/metabolismo
11.
Circ Res ; 109(7): 739-49, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21835911

RESUMO

RATIONALE: Peroxiredoxin 2 (Prdx2), a thiol-specific peroxidase, has been reported to regulate proinflammatory responses, vascular remodeling, and global oxidative stress. OBJECTIVE: Although Prdx2 has been proposed to retard atherosclerosis development, no direct evidence and mechanisms have been reported. METHODS AND RESULTS: We show that Prdx2 is highly expressed in endothelial and immune cells in atherosclerotic lesions and blocked the increase of endogenous H(2)O(2) by atherogenic stimulation. Deficiency of Prdx2 in apolipoprotein E-deficient (ApoE(-/-)) mice accelerated plaque formation with enhanced activation of p65, c-Jun, JNKs, and p38 mitogen-activated protein kinase; and these proatherogenic effects of Prdx2 deficiency were rescued by administration of the antioxidant ebselen. In bone marrow transplantation experiments, we found that Prdx2 has a major role in inhibiting atherogenic responses in both vascular and immune cells. Prdx2 deficiency resulted in increased expression of vascular adhesion molecule-1, intercellular adhesion molecule-1, and monocyte chemotactic protein-1, which led to increased immune cell adhesion and infiltration into the aortic intima. Compared with deficiency of glutathione peroxidase 1 or catalase, Prdx2 deficiency showed a severe predisposition to develop atherosclerosis. CONCLUSIONS: Prdx2 is a specific peroxidase that inhibits atherogenic responses in vascular and inflammatory cells, and specific activation of Prdx2 may be an effective means of antiatherogenic therapy.


Assuntos
Aorta/enzimologia , Apolipoproteínas E/deficiência , Aterosclerose/enzimologia , Peroxirredoxinas/deficiência , Animais , Antioxidantes/farmacologia , Aorta/efeitos dos fármacos , Aorta/imunologia , Aorta/patologia , Apolipoproteínas E/genética , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Aterosclerose/prevenção & controle , Azóis/farmacologia , Células da Medula Óssea/enzimologia , Transplante de Medula Óssea , Catalase/genética , Catalase/metabolismo , Quimiocina CCL2/metabolismo , Modelos Animais de Doenças , Células Endoteliais/enzimologia , Glutationa Peroxidase/deficiência , Glutationa Peroxidase/genética , Peróxido de Hidrogênio/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Isoindóis , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compostos Organosselênicos/farmacologia , Peroxirredoxinas/genética , Índice de Gravidade de Doença , Transdução de Sinais , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Glutationa Peroxidase GPX1
12.
J Lipid Atheroscler ; 12(2): 132-151, 2023 May.
Artigo em Inglês | MEDLINE | ID: mdl-37265853

RESUMO

Precise redox balance is essential for the optimum health and physiological function of the human body. Furthermore, an unbalanced redox state is widely believed to be part of numerous diseases, ultimately resulting in death. In this review, we discuss the relationship between redox balance and cardiovascular disease (CVD). In various animal models, excessive oxidative stress has been associated with increased atherosclerotic plaque formation, which is linked to the inflammation status of several cell types. However, various antioxidants can defend against reactive oxidative stress, which is associated with an increased risk of CVD and mortality. The different cardiovascular effects of these antioxidants are presumably due to alterations in the multiple pathways that have been mechanistically linked to accelerated atherosclerotic plaque formation, macrophage activation, and endothelial dysfunction in animal models of CVD, as well as in in vitro cell culture systems. Autophagy is a regulated cell survival mechanism that removes dysfunctional or damaged cellular organelles and recycles the nutrients for the generation of energy. Furthermore, in response to atherogenic stress, such as the generation of reactive oxygen species, oxidized lipids, and inflammatory signaling between cells, autophagy protects against plaque formation. In this review, we characterize the broad spectrum of oxidative stress that influences CVD, summarize the role of autophagy in the content of redox balance-associated pathways in atherosclerosis, and discuss potential therapeutic approaches to target CVD by stimulating autophagy.

13.
Methods Mol Biol ; 2662: 183-192, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37076681

RESUMO

In the research setting, white adipose tissue (WAT) transplantation, also known as fat transplantation, is often used to understand the physiological function of adipocytes or associated stromal vascular cells such as macrophages in the context of local and systemic metabolism. The mouse is the most common animal model used where WAT from a donor is transferred either to a subcutaneous site of the same organism or to a subcutaneous region of a recipient. Here, we describe in detail the procedure for heterologous fat transplantation, and, given the need for survival surgery, peri- and postoperative care and subsequent histological confirmation of fat grafts will also be discussed.


Assuntos
Adipócitos , Tecido Adiposo Branco , Camundongos , Animais , Tecido Adiposo Branco/metabolismo , Adipócitos/metabolismo , Modelos Animais , Tecido Adiposo/irrigação sanguínea
14.
Osong Public Health Res Perspect ; 14(4): 252-262, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37652680

RESUMO

BACKGROUND: This study aimed to examine the scale, characteristics, risk factors, and modes of transmission in a coronavirus disease 2019 (COVID-19) outbreak at a high school in Seoul, Republic of Korea. METHODS: An epidemiological survey was conducted of 1,118 confirmed cases and close contacts from a COVID-19 outbreak at an educational facility starting on May 31, 2021. In-depth interviews, online questionnaires, flow evaluations, and CCTV analyses were used to devise infection prevention measures. Behavioral and spatial risk factors were identified, and statistical significance was tested. RESULTS: Among 3rd-year students, there were 33 confirmed COVID-19 cases (9.6%). Students who used a study room in the annex building showed a statistically significant 4.3-fold elevation in their relative risk for infection compared to those who did not use the study room. Moreover, CCTV facial recognition analysis confirmed that 17.8% of 3rd-year students did not wear masks and had the lowest percentage of mask-wearers by grade. The air epidemiological survey conducted in the study room in the annex, which met the 3 criteria for a closed space, confirmed that there was only 10% natural ventilation due to the poor ventilation system. CONCLUSION: To prevent and manage the spread of COVID-19 in educational facilities, advance measures that consider the size, operation, and resources of each school are crucial. In addition, various survey methodologies should be used in future studies to quickly analyze a wider range of data that can inform an evidence-based quarantine response.

15.
Autophagy ; 19(3): 886-903, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35982578

RESUMO

Dysfunction in the macrophage lysosomal system including reduced acidity and diminished degradative capacity is a hallmark of atherosclerosis, leading to blunted clearance of excess cellular debris and lipids in plaques and contributing to lesion progression. Devising strategies to rescue this macrophage lysosomal dysfunction is a novel therapeutic measure. Nanoparticles have emerged as an effective platform to both target specific tissues and serve as drug delivery vehicles. In most cases, administered nanoparticles are taken up non-selectively by the mononuclear phagocyte system including monocytes/macrophages leading to the undesirable degradation of cargo in lysosomes. We took advantage of this default route to target macrophage lysosomes to rectify their acidity in disease states such as atherosclerosis. Herein, we develop and test two commonly used acidic nanoparticles, poly-lactide-co-glycolic acid (PLGA) and polylactic acid (PLA), both in vitro and in vivo. Our results in cultured macrophages indicate that the PLGA-based nanoparticles are the most effective at trafficking to and enhancing acidification of lysosomes. PLGA nanoparticles also provide functional benefits including enhanced lysosomal degradation, promotion of macroautophagy/autophagy and protein aggregate removal, and reduced apoptosis and inflammasome activation. We demonstrate the utility of this system in vivo, showing nanoparticle accumulation in, and lysosomal acidification of, macrophages in atherosclerotic plaques. Long-term administration of PLGA nanoparticles results in significant reductions in surrogates of plaque complexity with reduced apoptosis, necrotic core formation, and cytotoxic protein aggregates and increased fibrous cap formation. Taken together, our data support the use of acidic nanoparticles to rescue macrophage lysosomal dysfunction in the treatment of atherosclerosis.Abbreviations: BCA: brachiocephalic arteries; FACS: fluorescence activated cell sorting; FITC: fluorescein-5-isothiocyanatel; IL1B: interleukin 1 beta; LAMP: lysosomal associated membrane protein; LIPA/LAL: lipase A, lysosomal acid type; LSDs: lysosomal storage disorders; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MFI: mean fluorescence intensity; MPS: mononuclear phagocyte system; PEGHDE: polyethylene glycol hexadecyl ether; PLA: polylactic acid; PLGA: poly-lactide-co-glycolic acid; SQSTM1/p62: sequestosome 1.


Assuntos
Aterosclerose , Nanopartículas , Placa Aterosclerótica , Humanos , Autofagia , Aterosclerose/patologia , Macrófagos/metabolismo , Placa Aterosclerótica/patologia , Lisossomos/metabolismo , Ácidos/metabolismo , Poliésteres/metabolismo
16.
STAR Protoc ; 3(4): 101665, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36094885

RESUMO

Previous studies have demonstrated that a high-protein diet leads to increased atherosclerosis in mice, and that this adverse effect is caused by activation of macrophage mTORC1 signaling. Here, we provide a detailed protocol for the evaluation of diet-induced mTORC1 signaling in plaque macrophages in atherosclerosis-prone apolipoprotein E (ApoE) knockout (KO) mice. This protocol includes flow cytometry and immunofluorescence analysis of atherosclerotic macrophages that can be used to study the atherogenic potential of a variety of mTORC1 modulators. For complete details on the use and execution of this protocol, please refer to Zhang et al. (2020).


Assuntos
Aterosclerose , Camundongos , Animais , Citometria de Fluxo , Macrófagos , Camundongos Knockout , Imunofluorescência
17.
Front Cardiovasc Med ; 9: 792717, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35656400

RESUMO

Vimentin is a type III intermediate filament protein expressed in cells of mesenchymal origin. Vimentin has been thought to function mainly as a structural protein and roles of vimentin in other cellular processes have not been extensively studied. Our current study aims to reveal functions of vimentin in macrophage foam cell formation, the critical stage of atherosclerosis. We demonstrated that vimentin null (Vim -/ - ) mouse peritoneal macrophages take up less oxidized LDL (oxLDL) than vimentin wild type (Vim +/+) macrophages. Despite less uptake of oxLDL in Vim -/ - macrophages, Vim +/+ and Vim -/ - macrophages did not show difference in expression of CD36 known to mediate oxLDL uptake. However, CD36 localized in plasma membrane was 50% less in Vim -/ - macrophages than in Vim +/+ macrophages. OxLDL/CD36 interaction induced protein kinase A (PKA)-mediated vimentin (Ser72) phosphorylation. Cd36 -/ - macrophages did not exhibit vimentin phosphorylation (Ser72) in response to oxLDL. Experiments using phospho-mimetic mutation of vimentin revealed that macrophages with aspartate-substituted vimentin (V72D) showed more oxLDL uptake and membrane CD36. LDL receptor null (Ldlr -/ - ) mice reconstituted with Vim -/ - bone marrow fed a western diet for 15 weeks showed 43% less atherosclerotic lesion formation than Ldlr -/ - mice with Vim +/+ bone marrow. In addition, Apoe -/ -Vim- / - (double null) mice fed a western diet for 15 weeks also showed 57% less atherosclerotic lesion formation than Apoe -/ - and Vim +/+mice. We concluded that oxLDL via CD36 induces PKA-mediated phosphorylation of vimentin (Ser72) and phosphorylated vimentin (Ser72) directs CD36 trafficking to plasma membrane in macrophages. This study reveals a function of vimentin in CD36 trafficking and macrophage foam cell formation and may guide to establish a new strategy for the treatment of atherosclerosis.

18.
Redox Biol ; 54: 102347, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35688114

RESUMO

Ischemic stroke is the leading cause of immortal disability and death worldwide. For treatment in the acute phase, it is necessary to control excessive reactive oxygen species (ROS) damage during ischemia/reperfusion (I/R). Microglia are well known to be closely associated with excessive ROS response in the early stage of I/R. However, the precise roles of microglia associated with mitigating ROS damage, and molecular markers of heterogenetic microglia in the I/R damaged brain has not been clarified. Here, we identified a new type of microglia associated with stroke in the I/R injured brain. Single-cell RNA sequencing (scRNA-seq) was used to assess transcriptional changes of microglia and immune cells in the contralateral (CL) and ipsilateral (IL) hemispheres after transient middle cerebral artery occlusion (tMCAO) surgery to mimic ischemic stroke. We classified a unique type of microglia with enhanced antioxidant function and markers similar to those of disease-associated microglia (DAM), designated them as stroke-associated microglia (SAM). The representative antioxidant enzyme, Peroxiredoxin-1 (Prdx1), was predominantly expressed in SAM and mediated ROS defense genes, including Txn1, Srx1, Mt1, and Mt2. In the Prdx1-/- I/R damaged brain, we observed significantly increased infarction, as assessed by TTC staining, and FACS analysis detected severe microglial cell death. Importantly, scRNA transcriptomics data showed that the SAM population was specifically decreased in Prdx1-/- mice and that these mice exhibited decreased ROS damage resistance. Inflammatory responses which were detected by ELISA and qPCR, were also increased in Prdx1-/- IL hemispheres. Finally, Prdx1-dependent antioxidative SAM were found to be essential for increasing the transcription levels of stroke-protective molecules, such as osteopontin and ferritin. A novel microglia type (SAM) is specifically activated in response to stroke I/R injury, and that Prdx1 expression is required for the activation and enhanced antioxidant function of SAM.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Peroxirredoxinas , Acidente Vascular Cerebral , Animais , Antioxidantes/metabolismo , Isquemia Encefálica/genética , Isquemia Encefálica/metabolismo , AVC Isquêmico/genética , Camundongos , Microglia/metabolismo , Peroxirredoxinas/genética , Peroxirredoxinas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/metabolismo
19.
J Clin Med ; 11(22)2022 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-36431192

RESUMO

Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multiorgan manifestations, including pleuropulmonary involvement (20-90%). The precise mechanism of pleuropulmonary involvement in SLE is not well-understood; however, systemic type 1 interferons, circulating immune complexes, and neutrophils seem to play essential roles. There are eight types of pleuropulmonary involvement: lupus pleuritis, pleural effusion, acute lupus pneumonitis, shrinking lung syndrome, interstitial lung disease, diffuse alveolar hemorrhage (DAH), pulmonary arterial hypertension, and pulmonary embolism. DAH has a high mortality rate (68-75%). The diagnostic tools for pleuropulmonary involvement in SLE include chest X-ray (CXR), computed tomography (CT), pulmonary function tests (PFT), bronchoalveolar lavage, biopsy, technetium-99m hexamethylprophylene amine oxime perfusion scan, and (18)F-fluorodeoxyglucose positron emission tomography. An approach for detecting pleuropulmonary involvement in SLE includes high-resolution CT, CXR, and PFT. Little is known about specific therapies for pleuropulmonary involvement in SLE. However, immunosuppressive therapies such as corticosteroids and cyclophosphamide are generally used. Rituximab has also been successfully used in three of the eight pleuropulmonary involvement forms: lupus pleuritis, acute lupus pneumonitis, and shrinking lung syndrome. Pleuropulmonary manifestations are part of the clinical criteria for SLE diagnosis. However, no review article has focused on the involvement of pleuropulmonary disease in SLE. Therefore, this article summarizes the literature on the epidemiology, pathogenesis, diagnosis, and management of pleuropulmonary involvement in SLE.

20.
Circulation ; 121(9): 1124-33, 2010 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-20176988

RESUMO

BACKGROUND: The tumor necrosis factor receptor superfamily, which includes CD40, LIGHT, and OX40, plays important roles in atherosclerosis. CD137 (4-1BB), a member of the tumor necrosis factor receptor superfamily, has been reported to be expressed in human atherosclerotic lesions. However, limited information is available on the precise role of CD137 in atherosclerosis and the effects of blocking CD137/CD137 ligand signaling on lesion formation. METHODS AND RESULTS: We generated CD137-deficient apolipoprotein E-knockout mice (ApoE(-/-) CD137(-/-)) and LDL-receptor-knockout mice (Ldlr(-/-)CD137(-/-)) to investigate the role of CD137 in atherogenesis. The deficiency of CD137 induced a reduction in atherosclerotic plaque lesions in both atherosclerosis mouse models, which was attributed to the downregulation of cytokines such as interferon-gamma, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha. CD137 signaling promoted the production of inflammatory molecules, including monocyte chemoattractant protein-1, interleukin-6, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1, in endothelial cells. Stimulation of CD137 ligand signaling activated monocytes/macrophages and augmented the production of proinflammatory cytokines in atherosclerotic vessels. CONCLUSIONS: CD137/CD137 ligand signaling plays multiple roles in the progression of atherosclerosis, and thus, blockade of this pathway is a promising therapeutic target for the disease.


Assuntos
Ligante 4-1BB/fisiologia , Aterosclerose/prevenção & controle , Hipercolesterolemia/complicações , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/fisiologia , Animais , Animais Congênicos , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/etiologia , Aterosclerose/imunologia , Cruzamentos Genéticos , Citocinas/biossíntese , Citocinas/genética , Dieta Aterogênica , Modelos Animais de Doenças , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Retroalimentação Fisiológica , Feminino , Hipercolesterolemia/genética , Mediadores da Inflamação/metabolismo , Interferon gama/imunologia , Ativação Linfocitária , Ativação de Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de LDL/deficiência , Receptores de LDL/genética , Transdução de Sinais , Linfócitos T/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/deficiência , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética
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