RESUMO
BACKGROUND: The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. METHODS: AngII (angiotensin II) was infused in Apoe-/- to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. RESULTS: Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe-/- mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1-deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6Chi monocytes, and γδ T cells. Sm22Cre+Wnk1lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-ß (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-ß blockade using neutralizing anti-TGF-ß antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1lox/lox mice but not in control animals. CONCLUSION: Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.
Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal , Aortite , Músculo Liso Vascular , Miócitos de Músculo Liso , Proteína Quinase 1 Deficiente de Lisina WNK , Animais , Aortite/genética , Aortite/metabolismo , Aortite/patologia , Camundongos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , Miócitos de Músculo Liso/patologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Humanos , Proteína Quinase 1 Deficiente de Lisina WNK/genética , Proteína Quinase 1 Deficiente de Lisina WNK/metabolismo , Camundongos Endogâmicos C57BL , Masculino , Células Cultivadas , Camundongos Knockout para ApoE , Modelos Animais de Doenças , Inflamação/metabolismo , Inflamação/genética , Inflamação/patologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologiaRESUMO
BACKGROUND: Ischemic cardiovascular diseases, particularly acute myocardial infarction (MI), is one of the leading causes of mortality worldwide. Indoleamine 2, 3-dioxygenase 1 (IDO) catalyzes 1 rate-limiting step of L-tryptophan metabolism, and emerges as an important regulator of many pathological conditions. We hypothesized that IDO could play a key role to locally regulate cardiac homeostasis after MI. METHODS: Cardiac repair was analyzed in mice harboring specific endothelial or smooth muscle cells or cardiomyocyte or myeloid cell deficiency of IDO and challenged with acute myocardial infarction. RESULTS: We show that kynurenine generation through IDO is markedly induced after MI in mice. Total genetic deletion or pharmacological inhibition of IDO limits cardiac injury and cardiac dysfunction after MI. Distinct loss of function of IDO in smooth muscle cells, inflammatory cells, or cardiomyocytes does not affect cardiac function and remodeling in infarcted mice. In sharp contrast, mice harboring endothelial cell-specific deletion of IDO show an improvement of cardiac function as well as cardiomyocyte contractility and reduction in adverse ventricular remodeling. In vivo kynurenine supplementation in IDO-deficient mice abrogates the protective effects of IDO deletion. Kynurenine precipitates cardiomyocyte apoptosis through reactive oxygen species production in an aryl hydrocarbon receptor-dependent mechanism. CONCLUSIONS: These data suggest that IDO could constitute a new therapeutic target during acute MI.
Assuntos
Células Endoteliais/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/uso terapêutico , Cinurenina/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Animais , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/farmacologia , Cinurenina/farmacologia , Camundongos , Infarto do Miocárdio/fisiopatologiaRESUMO
Cardiovascular disease (CVD) is one of the major causes of mortality worldwide. Inflammation is the underlying common mechanism involved in CVD. It has been recently related to amino acid metabolism, which acts as a critical regulator of innate and adaptive immune responses. Among different metabolites that have emerged as important regulators of immune and inflammatory responses, tryptophan (Trp) metabolites have been shown to play a pivotal role in CVD. Here, we provide an overview of the fundamental aspects of Trp metabolism and the interplay between the dysregulation of the main actors involved in Trp metabolism such as indoleamine 2, 3-dioxygenase 1 (IDO) and CVD, including atherosclerosis and myocardial infarction. IDO has a prominent and complex role. Its activity, impacting on several biological pathways, complicates our understanding of its function, particularly in CVD, where it is still under debate. The discrepancy of the observed IDO effects could be potentially explained by its specific cell and tissue contribution, encouraging further investigations regarding the role of this enzyme. Thus, improving our understanding of the function of Trp as well as its derived metabolites will help to move one step closer towards tailored therapies aiming to treat CVD.
Assuntos
Doenças Cardiovasculares/metabolismo , Dieta , Triptofano/metabolismo , Doenças Cardiovasculares/terapia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Metaboloma , Modelos BiológicosRESUMO
RATIONALE: Despite an established role for adaptive immune responses in atherosclerosis, the contribution of dendritic cells (DCs) and their various subsets is still poorly understood. OBJECTIVE: Here, we address the role of IRF8 (interferon regulatory factor 8)-dependent DCs (lymphoid CD8α+ and their developmentally related nonlymphoid CD103+ DCs) in the induction of proatherogenic immune responses during high fat feeding. METHODS AND RESULTS: Using a fate-mapping technique to track DCs originating from a DNGR1+ (dendritic cell natural killer lectin group receptor 1) precursor (Clec9a+/creRosa+/EYFP mice), we first show that YFPhiCD11chiMHCIIhi (major histocompatibility complex class II) DCs are present in the atherosclerotic aorta of low-density lipoprotein receptor-deficient (Ldlr-/-) mice and are CD11b-CD103+IRF8hi. Restricted deletion of IRF8 in DCs (Irf8flox/floxCd11cCre ) reduces the accumulation of CD11chiMHCIIhi DCs in the aorta without affecting CD11b+CD103- DCs or macrophages but completely abolishes the accumulation of aortic CD11b-CD103+ DCs. Lymphoid CD8α+ DCs are also deleted. This is associated with a significant reduction of aortic T-cell accumulation and a marked reduction of high-fat diet-induced systemic T-cell priming, activation, and differentiation toward T helper type 1 cells, T follicular helper cells, and regulatory T cells. As a consequence, B-cell activation and germinal center responses to high-fat diet are also markedly reduced. IRF8 deletion in DCs significantly reduces the development of atherosclerosis, predominantly in the aortic sinus, despite a modest increase in total plasma cholesterol levels. CONCLUSIONS: IRF8 expression in DCs plays a nonredundant role in the development of proatherogenic adaptive immunity.
Assuntos
Imunidade Adaptativa , Aterosclerose/imunologia , Células Dendríticas/imunologia , Fatores Reguladores de Interferon/metabolismo , Animais , Aorta/citologia , Aterosclerose/etiologia , Antígenos CD11/genética , Antígenos CD11/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Feminino , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/metabolismo , Fatores Reguladores de Interferon/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T/imunologiaRESUMO
Objective- Recent studies suggested the occurrence of phenotypic switching of vascular smooth muscle cells (VSMCs) during the development of aortic aneurysm (AA). However, lineage-tracing studies are still lacking, and the behavior of VSMCs during the formation of dissecting AA is poorly understood. Approach and Results- We used multicolor lineage tracing of VSMCs to track their fate after injury in murine models of Ang II (angiotensin II)-induced dissecting AA. We also addressed the direct impact of autophagy on the response of VSMCs to AA dissection. Finally, we studied the relevance of these processes to human AAs. Here, we show that a subset of medial VSMCs undergoes clonal expansion and that VSMC outgrowths are observed in the adventitia and borders of the false channel during Ang II-induced development of dissecting AA. The clonally expanded VSMCs undergo phenotypic switching with downregulation of VSMC differentiation markers and upregulation of phagocytic markers, indicative of functional changes. In particular, autophagy and endoplasmic reticulum stress responses are activated in the injured VSMCs. Loss of autophagy in VSMCs through deletion of autophagy protein 5 gene ( Atg5) increases the susceptibility of VSMCs to death, enhances endoplasmic reticulum stress activation, and promotes IRE (inositol-requiring enzyme) 1α-dependent VSMC inflammation. These alterations culminate in increased severity of aortic disease and higher incidence of fatal AA dissection in mice with VSMC-restricted deletion of Atg5. We also report increased expression of autophagy and endoplasmic reticulum stress markers in VSMCs of human dissecting AAs. Conclusions- VSMCs undergo clonal expansion and phenotypic switching in Ang II-induced dissecting AAs in mice. We also identify a critical role for autophagy in regulating VSMC death and endoplasmic reticulum stress-dependent inflammation with important consequences for aortic wall homeostasis and repair.
Assuntos
Aneurisma Aórtico/patologia , Dissecção Aórtica/patologia , Autofagia , Plasticidade Celular , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Adulto , Idoso , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/metabolismo , Angiotensina II , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/metabolismo , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Linhagem da Célula , Células Cultivadas , Modelos Animais de Doenças , Endorribonucleases/metabolismo , Feminino , Humanos , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Fenótipo , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de SinaisRESUMO
RATIONALE: Necrotic core formation during the development of atherosclerosis is associated with a chronic inflammatory response and promotes accelerated plaque development and instability. However, the molecular links between necrosis and the development of atherosclerosis are not completely understood. Clec9a (C-type lectin receptor) or DNGR-1 (dendritic cell NK lectin group receptor-1) is preferentially expressed by the CD8α+ subset of dendritic cells (CD8α+ DCs) and is involved in sensing necrotic cells. We hypothesized that sensing of necrotic cells by DNGR-1 plays a determinant role in the inflammatory response of atherosclerosis. OBJECTIVE: We sought to address the impact of total, bone marrow-restricted, or CD8α+ DC-restricted deletion of DNGR-1 on atherosclerosis development. METHODS AND RESULTS: We show that total absence of DNGR-1 in Apoe (apolipoprotein e)-deficient mice (Apoe-/-) and bone marrow-restricted deletion of DNGR-1 in Ldlr (low-density lipoprotein receptor)-deficient mice (Ldlr-/-) significantly reduce inflammatory cell content within arterial plaques and limit atherosclerosis development in a context of moderate hypercholesterolemia. This is associated with a significant increase of the expression of interleukin-10 (IL-10). The atheroprotective effect of DNGR-1 deletion is completely abrogated in the absence of bone marrow-derived IL-10. Furthermore, a specific deletion of DNGR-1 in CD8α+ DCs significantly increases IL-10 expression, reduces macrophage and T-cell contents within the lesions, and limits the development of atherosclerosis. CONCLUSIONS: Our results unravel a new role of DNGR-1 in regulating vascular inflammation and atherosclerosis and potentially identify a new target for disease modulation.
Assuntos
Aterosclerose/metabolismo , Aterosclerose/patologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Interleucina-10/biossíntese , Lectinas Tipo C/deficiência , Receptores Imunológicos/deficiência , Animais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
OBJECTIVE: Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFß (transforming growth factor-ß) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. APPROACH AND RESULTS: Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFß using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFß blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1ß or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1ß after disease initiation has no effect on AAA progression to rupture. CONCLUSIONS: Endogenous TGFß activity is required for the healing of AAA. TGFß blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.
Assuntos
Anticorpos Monoclonais/toxicidade , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Elastase Pancreática , Fator de Crescimento Transformador beta/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/imunologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Interleucina-1beta/metabolismo , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síncrotrons , Trombose/induzido quimicamente , Trombose/metabolismo , Trombose/patologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Ultrassonografia , Cicatrização/efeitos dos fármacosRESUMO
Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins and components of the injured vascular wall. Specific T lymphocyte responses driven by T helper-1 or T regulatory cells play distinct and opposing roles in atherosclerosis. More recently, T helper-17 cells, which produce the prototype cytokine interleukin-17, have been characterized and shown to be critical in mucosal host defense against microbial and fungal pathogens. Sustained production of interleukin-17 in an inflammatory context has been linked to the pathology of several autoimmune and inflammatory diseases. However, regulatory and protective roles have also been reported in selective disease settings. Studies in atherosclerosis led to conflicting results on the roles of interleukin-17 and T helper-17 cells in disease development and plaque stability. The present review provides a summary of the available evidence and putative mechanisms linking this pathway to atherosclerosis, as well as a perspective on the risks and benefits of interleukin-17-targeted cytokine therapy in patients at high cardiovascular risk.
Assuntos
Aterosclerose/imunologia , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Interleucina-17/imunologia , Células Th17/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Aterosclerose/tratamento farmacológico , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Diferenciação Celular , Microambiente Celular , Desenho de Fármacos , Humanos , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Interleucina-17/genética , Interleucina-17/metabolismo , Terapia de Alvo Molecular , Placa Aterosclerótica , Transdução de Sinais , Células Th17/efeitos dos fármacos , Células Th17/metabolismoRESUMO
OBJECTIVE: Mutations of signal transducer and activator of transcription 3 (STAT3) are responsible for autosomal dominant hyperimmunoglobulin E syndrome. Recently, we reported frequent vascular abnormalities, including aneurysms in these patients, and demonstrated that STAT3 inhibition promoted aneurysm in mice. The purpose of this study was to investigate the role of cell-specific STAT3 signaling in the susceptibility to aneurysm. METHODS AND RESULTS: C57BL/6 wild-type mice were irradiated and repopulated with bone marrow cells isolated from either wild-type mice or from mice with defective STAT3 signaling as a result of overexpression of suppressor of cytokine signaling 3 (SOCS3-Tg mice). Mice were then subjected to a validated model of abdominal aortic aneurysm induced by angiotensin II infusion for 28 days, along with repetitive injections of a neutralizing antitransforming growth factor-ß antibody. We found that overexpression of SOCS3 in bone marrow-derived cells significantly increased aneurysm severity (P=0.04). In contrast, overexpression of SOCS3 in the vessel wall had no effect on the disease process. Surprisingly, deletion of STAT3 signaling in macrophages did not affect aneurysm development. Interestingly, however, defective STAT3 signaling in SOCS3-Tg T cells markedly increased aneurysm severity (P=0.01) and mortality from aneurysm rupture (P=0.008). Overexpression of SOCS3 in T cells significantly decreased interleukin-17 production (P<0.0001) and was associated with a reduction of its plasma levels (P=0.02). CONCLUSIONS: These findings clearly identify a central role for T cell-specific STAT3 signaling in the promotion of vascular aneurysm and support previous work on interleukin-17 protective role in this process.
Assuntos
Aneurisma da Aorta Abdominal/metabolismo , Interleucina-17/metabolismo , Proteínas Supressoras da Sinalização de Citocina/metabolismo , Células Th17/metabolismo , Angiotensina II , Animais , Anticorpos Neutralizantes , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/imunologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Transplante de Medula Óssea , Células Cultivadas , Modelos Animais de Doenças , Genótipo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Fenótipo , Fator de Transcrição STAT3/deficiência , Fator de Transcrição STAT3/genética , Transdução de Sinais , Proteína 3 Supressora da Sinalização de Citocinas , Proteínas Supressoras da Sinalização de Citocina/genética , Células Th17/imunologia , Fatores de Tempo , Fator de Crescimento Transformador beta/imunologia , Regulação para Cima , Irradiação Corporal TotalRESUMO
AIM: Interleukin (IL)-17 pathway is being clinically targeted in immune-mediated diseases, most of which are associated with a significant cardiovascular risk. We investigated the relationship between serum levels of IL-17 and the risk of cardiovascular events in patients with acute myocardial infarction. METHODS AND RESULTS: We used data from 981 patients enrolled in the prospective, multicentre French registry of Acute ST elevation, or non-ST-elevation Myocardial Infarction (Fast-MI, NCT00673036). Serum levels of IL-17 were associated with the risk of all-cause death and recurrent MI at 2 years, with levels of IL-17 below the median indicative of a worse outcome. The impact of IL-17 remained significant after adjustment for known cardiovascular risk factors, C-reactive protein, and treatments including statins: hazard ratio (HR) = 1.40 (1.03-1.91); P = 0.03. IL-17 inhibited mononuclear cell adhesion to endothelium and reduced endothelial vascular cell adhesion molecule (VCAM-1) expression. Patients with low (below the median) IL-17 levels and high (above the median) soluble VCAM-1 (sVCAM-1) levels were at particularly increased risk of death and MI: adjusted HR = 2.22 (1.32-3.75) compared with the high IL-17/low sVCAM-1 group (P = 0.002). CONCLUSIONS: Low serum levels of IL-17 are associated with a higher risk of major cardiovascular events in Caucasian patients with acute MI. Our results raise possible concern about the use of inhibitors of the IL-17 pathway in clinical settings associated with a high cardiovascular risk. CLINICAL TRIALS REGISTRATION: NCT00673036.
Assuntos
Células Endoteliais da Veia Umbilical Humana/metabolismo , Interleucina-17/sangue , Leucócitos Mononucleares/metabolismo , Infarto do Miocárdio/sangue , Idoso , Análise de Variância , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-17/fisiologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Prognóstico , Estudos Prospectivos , Recidiva , Sistema de Registros , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Tryptophan (Trp) is an essential amino acid, whose metabolism is a key gatekeeper of intestinal homeostasis. Yet, its systemic effects, particularly on atherosclerosis, remain unknown. Here we show that high-fat diet (HFD) increases the activity of intestinal indoleamine 2, 3-dioxygenase 1 (IDO), which shifts Trp metabolism from the production of microbiota-derived indole metabolites towards kynurenine production. Under HFD, the specific deletion of IDO in intestinal epithelial cells leads to intestinal inflammation, impaired intestinal barrier, augmented lesional T lymphocytes and atherosclerosis. This is associated with an increase in serotonin production and a decrease in indole metabolites, thus hijacking Trp for the serotonin pathway. Inhibition of intestinal serotonin production or supplementation with indole derivatives alleviates plaque inflammation and atherosclerosis. In summary, we uncover a pivotal role of intestinal IDO in the fine-tuning of Trp metabolism with systemic effects on atherosclerosis, paving the way for new therapeutic strategies to relieve gut-associated inflammatory diseases.
Assuntos
Aterosclerose , Dieta Hiperlipídica , Indolamina-Pirrol 2,3,-Dioxigenase , Mucosa Intestinal , Camundongos Endogâmicos C57BL , Serotonina , Triptofano , Animais , Triptofano/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/metabolismo , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Aterosclerose/genética , Aterosclerose/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Camundongos , Serotonina/metabolismo , Mucosa Intestinal/metabolismo , Cinurenina/metabolismo , Masculino , Microbioma Gastrointestinal , Indóis/farmacologia , Inflamação/metabolismo , Camundongos Knockout , Intestinos/patologia , Linfócitos T/metabolismo , Linfócitos T/imunologia , Modelos Animais de DoençasRESUMO
Although high-fat diet (HFD)-induced gut microbiota dysbiosis is known to affect atherosclerosis, the underlying mechanisms remain to be fully explored. Here, we show that the progression of atherosclerosis depends on a gut microbiota shaped by an HFD but not a high-cholesterol (HC) diet and, more particularly, on low fiber (LF) intake. Mechanistically, gut lymphoid cells impacted by HFD- or LF-induced microbiota dysbiosis highly proliferate in mesenteric lymph nodes (MLNs) and migrate from MLNs to the periphery, which fuels T cell accumulation within atherosclerotic plaques. This is associated with the induction of mucosal addressin cell adhesion molecule 1 (MAdCAM-1) within plaques and the presence of enterotropic lymphocytes expressing ß7 integrin. MLN resection or lymphocyte deficiency abrogates the pro-atherogenic effects of a microbiota shaped by LF. Our study shows a pathological link between a diet-shaped microbiota, gut immune cells, and atherosclerosis, suggesting that a diet-modulated microbiome might be a suitable therapeutic target to prevent atherosclerosis.
Assuntos
Aterosclerose , Microbiota , Placa Aterosclerótica , Humanos , Animais , Camundongos , Disbiose/induzido quimicamente , Linfócitos , Dieta Hiperlipídica/efeitos adversos , Camundongos Endogâmicos C57BLRESUMO
Caspase recruitment-domain containing protein 9 (CARD9) is a key signaling pathway in macrophages but its role in atherosclerosis is still poorly understood. Global deletion of Card9 in Apoe-/- mice as well as hematopoietic deletion in Ldlr-/- mice increases atherosclerosis. The acceleration of atherosclerosis is also observed in Apoe-/-Rag2-/-Card9-/- mice, ruling out a role for the adaptive immune system in the vascular phenotype of Card9 deficient mice. Card9 deficiency alters macrophage phenotype through CD36 overexpression with increased IL-1ß production, increased lipid uptake, higher cell death susceptibility and defective autophagy. Rapamycin or metformin, two autophagy inducers, abolish intracellular lipid overload, restore macrophage survival and autophagy flux in vitro and finally abolish the pro-atherogenic effects of Card9 deficiency in vivo. Transcriptomic analysis of human CARD9-deficient monocytes confirms the pathogenic signature identified in murine models. In summary, CARD9 is a key protective pathway in atherosclerosis, modulating macrophage CD36-dependent inflammatory responses, lipid uptake and autophagy.
Assuntos
Aterosclerose , Humanos , Animais , Camundongos , Aterosclerose/metabolismo , Autofagia/genética , Apolipoproteínas E/genética , Lipídeos , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Camundongos Knockout , Camundongos Endogâmicos C57BLRESUMO
Atherosclerosis is a chronic inflammatory disease of the arterial wall driven by innate and adaptive immune responses. Inflammation controls the development and the destabilization of arterial plaque. Cells involved in the atherosclerotic process secrete and are activated by soluble factors, known as cytokines. Important recent advances in the comprehension of the mechanisms of atherosclerosis have provided evidence for a dual role of cytokines: proinflammatory and T helper-1-related cytokines promote the development and progression of the disease, whereas antiinflammatory and regulatory T cell-related cytokines exert clear antiatherogenic activities. This review focuses on recent advances regarding the role of cytokines, with the exception of chemokines, in the development, progression, and complications of atherosclerosis.
Assuntos
Aterosclerose/imunologia , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Inflamação/imunologia , Transdução de Sinais , Animais , Aterosclerose/complicações , Progressão da Doença , Humanos , Inflamação/complicaçõesRESUMO
Introduction: Amine oxidase copper containing 3 (AOC3) displays adhesion between leukocytes and endothelial cells and enzymatic functions. Given its controversial role in atherogenesis, we proposed to investigate the involvement of AOC3 in the formation of atherosclerotic plaques in ApoE-/-AOC3-/- mice and human coronary arteries. Methods: Lesions, contractile markers, and AOC3 were studied in aortic tissues from 15- and 25-week-old mice and different stages of human coronary atherosclerotic arteries by immunohistochemistry (IHC) and/or western blot. Human VSMCs, treated or not with LJP1586, an AOC3 inhibitor, were used to measure differentiation markers by qPCR. AOC3 co-localization with specific cell markers was studied by using confocal microscopy in mice and human samples. Results: At 15 weeks old, the absence of AOC3 was associated with increased lesion size, α-SMA, and CD3 staining in the plaque independently of a cholesterol modification. At 25 weeks old, advanced plaques were larger with equivalent staining for α-SMA while CD3 increased in the media from ApoE-/-AOC3-/- mice. At both ages, the macrophage content of the lesion was not modified. Contractile markers decreased whereas MCP-1 appeared augmented only in the 15-week-old ApoE-/-AOC3. AOC3 is mainly expressed by mice and human VSMC is slightly expressed by endothelium but not by macrophages. Conclusion: AOC3 knock-out increased atherosclerotic plaques at an early stage related to a VSMC dedifferentiation associated with a higher T cells recruitment in plaques explained by the MCP-1 augmentation. This suggests that AOC3 may have an important role in atherosclerosis independent of its canonical inflammatory effect. The dual role of AOC3 impacts therapeutic strategies using pharmacological regulators of SSAO activity.
RESUMO
JAK2V617F mutation is associated with an increased risk for athero-thrombotic cardiovascular disease, but its role in aortic disease development and complications remains unknown. In a cohort of patients with myeloproliferative neoplasm, JAK2V617F mutation was identified as an independent risk factor for dilation of both the ascending and descending thoracic aorta. Using single-cell RNA-seq, complementary genetically-modified mouse models, as well as pharmacological approaches, we found that JAK2V617F mutation was associated with a pathogenic pro-inflammatory phenotype of perivascular tissue-resident macrophages, which promoted deleterious aortic wall remodeling at early stages, and dissecting aneurysm through the recruitment of circulating monocytes at later stages. Finally, genetic manipulation of tissue-resident macrophages, or treatment with a Jak2 inhibitor, ruxolitinib, mitigated aortic wall inflammation and reduced aortic dilation and rupture. Overall, JAK2V617F mutation drives vascular resident macrophages toward a pathogenic phenotype and promotes dissecting aortic aneurysm.
Assuntos
Aneurisma Aórtico , Dissecção Aórtica , Camundongos , Animais , Dissecção Aórtica/patologia , Fenótipo , Mutação , Macrófagos/patologia , Aneurisma Aórtico/genética , Aneurisma Aórtico/complicaçõesRESUMO
PURPOSE OF REVIEW: To summarize the current knowledge on the origin and physiological function of T helper 17 (Th17) and discuss the contrasting results pertaining to the role of Th17 and interleukin-17 (IL-17) in atherosclerosis. RECENT FINDINGS: Atherosclerosis is a chronic inflammatory arterial disease driven by both innate and adaptive immune responses to modified lipoproteins. Although initial studies have focused on the role of Th1 and Th2 responses in atherosclerosis, more recent findings identified atheroprotective roles for several subsets of regulatory T cells. Th17 represents a new T-cell lineage with important roles in the clearance of pathogenic bacteria and fungi. The increase of Th17 and IL-17 has been recently linked to the pathogenesis of several autoimmune diseases. However, its role in chronic inflammatory diseases such as atherosclerosis remains poorly understood. The few studies available on this topic have generated contrasting results, which could be attributed to different approaches used on various mouse models. SUMMARY: IL-17 seems to have a modulatory role in atherosclerosis. Future studies are needed to better determine the molecular mechanisms involved in this regulation and examine whether targeting IL-17 pathway will be useful to treat cardiovascular diseases.
Assuntos
Aterosclerose/metabolismo , Interleucina-17/metabolismo , Animais , Aterosclerose/imunologia , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Humanos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismoRESUMO
The triggering receptor expressed on myeloid cells 1 (TREM-1) drives inflammatory responses in several cardiovascular diseases but its role in abdominal aortic aneurysm (AAA) remains unknown. Our objective was to explore the role of TREM-1 in a mouse model of angiotensin II-induced (AngII-induced) AAA. TREM-1 expression was detected in mouse aortic aneurysm and colocalized with macrophages. Trem1 gene deletion (Apoe-/-Trem1-/-), as well as TREM-1 pharmacological blockade with LR-12 peptide, limited both AAA development and severity. Trem1 gene deletion attenuated the inflammatory response in the aorta, with a reduction of Il1b, Tnfa, Mmp2, and Mmp9 mRNA expression, and led to a decreased macrophage content due to a reduction of Ly6Chi classical monocyte trafficking. Conversely, antibody-mediated TREM-1 stimulation exacerbated Ly6Chi monocyte aorta infiltration after AngII infusion through CD62L upregulation and promoted proinflammatory signature in the aorta, resulting in worsening AAA severity. AngII infusion stimulated TREM-1 expression and activation on Ly6Chi monocytes through AngII receptor type I (AT1R). In human AAA, TREM-1 was detected and TREM1 mRNA expression correlated with SELL mRNA expression. Finally, circulating levels of sTREM-1 were increased in patients with AAA when compared with patients without AAA. In conclusion, TREM-1 is involved in AAA pathophysiology and may represent a promising therapeutic target in humans.
Assuntos
Angiotensina II/efeitos adversos , Aneurisma da Aorta Abdominal/metabolismo , Movimento Celular/efeitos dos fármacos , Monócitos/metabolismo , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Angiotensina II/farmacologia , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Movimento Celular/genética , Deleção de Genes , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Camundongos , Camundongos Knockout para ApoE , Monócitos/patologia , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CONTEXT: Recent studies reported that retinol-binding protein 4 (RBP4) has a causal role in insulin resistance and suggested that its circulating levels may predict cardiovascular disease. However, the latter assumption has not yet been tested. OBJECTIVE: We assessed the value of RBP4 measurement in the prediction of incident coronary artery disease (CAD). DESIGN: We conducted a nested case-control study of incident CAD (n = 1036 cases vs. n = 1889 controls) selected from among 25,336 participants of the EPIC-Norfolk study. SETTING: Healthy men and women, aged between 45 and 79 yr, were recruited from age-sex registers of general practices in Norfolk. PATIENTS AND OTHER PARTICIPANTS: Participants completed a baseline questionnaire survey between 1993 and 1997, attended a clinic visit, and were followed for an average of 6 yr. Cases (n = 1036) were participants who developed CAD during the follow-up. Controls (n = 1889) matched by age, sex, and enrollment time remained free of any CAD during follow-up. MAIN OUTCOMES MEASURE: Risk of incident fatal or nonfatal CAD according to RBP4 quartiles was assessed. RESULTS: RBP4 levels were higher in cases than in controls. RBP4 levels correlated weakly with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, and total and low-density lipoprotein-cholesterol and were inversely associated with C-reactive protein concentrations. The strongest correlation was found with triglycerides. The risk of incident CAD was associated with increasing quartiles of RBP4 levels (P = 0.03). However, adjustment for cardiovascular risk factors abolished this association. CONCLUSIONS: Measurement of serum RBP4 does not provide added value for predicting CAD risk beyond traditional risk factors.
Assuntos
Doença da Artéria Coronariana/etiologia , Proteínas Plasmáticas de Ligação ao Retinol/análise , Idoso , Estudos de Casos e Controles , HDL-Colesterol/sangue , Doença da Artéria Coronariana/sangue , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The intestine has a major role in the digestion and absorption of nutrients, and gut barrier is the first defense line against harmful pathogens. Alteration of the intestinal barrier is associated with enhanced intestinal permeability and development of numerous pathological diseases including gastrointestinal and cardiometabolic diseases. Among the metabolites that play an important role within intestinal health, L Tryptophan (Trp) is one of the nine essential amino acids supplied by diet, whose metabolism appears as a key modulator of gut microbiota, with major impacts on physiological, and pathological pathways. Recently, emerging evidence showed that the Trp catabolism through one major enzyme indoleamine 2,3-dioxygenase 1 (IDO1) expressed by the host affects Trp metabolism by gut microbiota to generate indole metabolites, thereby altering gut function and health in mice and humans. In this mini review, I summarize the most recent advances concerning the role of Trp metabolism in host-microbiota cross-talk in health, and metabolic diseases. This novel aspect of IDO1 function in intestine will better explain its complex roles in a broad range of disease states where the gut function affects local as well as systemic health, and will open new therapeutic strategies.