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1.
Biomed Pharmacother ; 139: 111668, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34243630

RESUMO

Metabolic Syndrome (MetS) is a complex and multifactorial condition often characterised by obesity, hypertension, hyperlipidaemia, insulin resistance, glucose intolerance and fasting hyperglycaemia. Collectively, MetS can increase the risk of atherosclerotic-cardiovascular disease, which is the leading cause of death worldwide. However, no animal model currently exists to study MetS in the context of atherosclerosis. In this study we developed a pre-clinical mouse model that recapitulates the spectrum of MetS features while developing atherosclerosis. When BPHx mice were placed on a western type diet for 16 weeks, all the classical characteristics of MetS were observed. Comprehensive metabolic analyses and atherosclerotic imaging revealed BPHx mice to be obese and hypertensive, with elevated total plasma cholesterol and triglyceride levels, that accelerated atherosclerosis. Altogether, we demonstrate that the BPHx mouse has all the major components of MetS, and accelerates the development of atherosclerosis.


Assuntos
Aterosclerose/patologia , Dieta/efeitos adversos , Hipertensão/patologia , Síndrome Metabólica/patologia , Animais , Aterosclerose/sangue , Aterosclerose/metabolismo , Glicemia/metabolismo , Colesterol/sangue , Modelos Animais de Doenças , Feminino , Intolerância à Glucose/sangue , Intolerância à Glucose/metabolismo , Intolerância à Glucose/patologia , Hipercolesterolemia/sangue , Hipercolesterolemia/metabolismo , Hipercolesterolemia/patologia , Hiperglicemia/sangue , Hiperglicemia/metabolismo , Hiperglicemia/patologia , Hiperlipidemias/sangue , Hiperlipidemias/metabolismo , Hiperlipidemias/patologia , Hipertensão/sangue , Hipertensão/metabolismo , Resistência à Insulina/fisiologia , Síndrome Metabólica/sangue , Síndrome Metabólica/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/metabolismo , Obesidade/patologia , Triglicerídeos/sangue
2.
Arterioscler Thromb Vasc Biol ; 41(3): 1167-1178, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33441028

RESUMO

OBJECTIVE: People with diabetes are at a significantly higher risk of cardiovascular disease, in part, due to accelerated atherosclerosis. Diabetic subjects have increased number of platelets that are activated, more reactive, and respond suboptimally to antiplatelet therapies. We hypothesized that reducing platelet numbers by inducing their premature apoptotic death would decrease atherosclerosis. Approach and Results: This was achieved by targeting the antiapoptotic protein Bcl-xL (B-cell lymphoma-extra large; which is essential for platelet viability) via distinct genetic and pharmacological approaches. In the former, we transplanted bone marrow from mice carrying the Tyr15 to Cys loss of function allele of Bcl-x (known as Bcl-xPlt20) or wild-type littermate controls into atherosclerotic-prone Ldlr+/- mice made diabetic with streptozotocin and fed a Western diet. Reduced Bcl-xL function in hematopoietic cells significantly decreased platelet numbers, exclusive of other hematologic changes. This led to a significant reduction in atherosclerotic lesion formation in Bcl-xPlt20 bone marrow transplanted Ldlr+/- mice. To assess the potential therapeutic relevance of reducing platelets in atherosclerosis, we next targeted Bcl-xL with a pharmacological strategy. This was achieved by low-dose administration of the BH3 (B-cell lymphoma-2 homology domain 3) mimetic, ABT-737 triweekly, in diabetic Apoe-/- mice for the final 6 weeks of a 12-week study. ABT-737 normalized platelet numbers along with platelet and leukocyte activation to that of nondiabetic controls, significantly reducing atherosclerosis while promoting a more stable plaque phenotype. CONCLUSIONS: These studies suggest that selectively reducing circulating platelets, by targeting Bcl-xL to promote platelet apoptosis, can reduce atherosclerosis and lower cardiovascular disease risk in diabetes. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/sangue , Aterosclerose/complicações , Plaquetas/patologia , Angiopatias Diabéticas/sangue , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Aterosclerose/prevenção & controle , Compostos de Bifenilo/administração & dosagem , Plaquetas/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/complicações , Feminino , Humanos , Leucócitos/patologia , Leucócitos/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitrofenóis/administração & dosagem , Piperazinas/administração & dosagem , Contagem de Plaquetas , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Risco , Sulfonamidas/administração & dosagem
3.
Diabetes ; 70(3): 772-787, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33323396

RESUMO

Low-grade persistent inflammation is a feature of diabetes-driven vascular complications, in particular activation of the Nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome to trigger the maturation and release of the inflammatory cytokine interleukin-1ß (IL-1ß). We investigated whether inhibiting the NLRP3 inflammasome, through the use of the specific small-molecule NLRP3 inhibitor MCC950, could reduce inflammation, improve vascular function, and protect against diabetes-associated atherosclerosis in the streptozotocin-induced diabetic apolipoprotein E-knockout mouse. Diabetes led to an approximately fourfold increase in atherosclerotic lesions throughout the aorta, which were significantly attenuated with MCC950 (P < 0.001). This reduction in lesions was associated with decreased monocyte-macrophage content, reduced necrotic core, attenuated inflammatory gene expression (IL-1ß, tumor necrosis factor-α, intracellular adhesion molecule 1, and MCP-1; P < 0.05), and reduced oxidative stress, while maintaining fibrous cap thickness. Additionally, vascular function was improved in diabetic vessels of mice treated with MCC950 (P < 0.05). In a range of cell lines (murine bone marrow-derived macrophages, human monocytic THP-1 cells, phorbol 12-myristate 13-acetate-differentiated human macrophages, and aortic smooth muscle cells from humans with diabetes), MCC950 significantly reduced IL-1ß and/or caspase-1 secretion and attenuated leukocyte-smooth muscle cell interactions under high glucose or lipopolysaccharide conditions. In summary, MCC950 reduces plaque development, promotes plaque stability, and improves vascular function, suggesting that targeting NLRP3-mediated inflammation is a novel therapeutic strategy to improve diabetes-associated vascular disease.


Assuntos
Aterosclerose/metabolismo , Inflamassomos/metabolismo , Miócitos de Músculo Liso/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Glicemia/metabolismo , Células Cultivadas , Imunofluorescência , Glucose/farmacologia , Humanos , Imuno-Histoquímica , Inflamassomos/genética , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Estresse Oxidativo/efeitos dos fármacos , Estresse Oxidativo/genética , Células THP-1 , Acetato de Tetradecanoilforbol/análogos & derivados , Acetato de Tetradecanoilforbol/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
4.
Circ Res ; 127(7): 877-892, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32564710

RESUMO

RATIONALE: Treatment efficacy for diabetes mellitus is largely determined by assessment of HbA1c (glycated hemoglobin A1c) levels, which poorly reflects direct glucose variation. People with prediabetes and diabetes mellitus spend >50% of their time outside the optimal glucose range. These glucose variations, termed transient intermittent hyperglycemia (TIH), appear to be an independent risk factor for cardiovascular disease, but the pathological basis for this association is unclear. OBJECTIVE: To determine whether TIH per se promotes myelopoiesis to produce more monocytes and consequently adversely affects atherosclerosis. METHODS AND RESULTS: To create a mouse model of TIH, we administered 4 bolus doses of glucose at 2-hour intervals intraperitoneally once to WT (wild type) or once weekly to atherosclerotic prone mice. TIH accelerated atherogenesis without an increase in plasma cholesterol, seen in traditional models of diabetes mellitus. TIH promoted myelopoiesis in the bone marrow, resulting in increased circulating monocytes, particularly the inflammatory Ly6-Chi subset, and neutrophils. Hematopoietic-restricted deletion of S100a9, S100a8, or its cognate receptor Rage prevented monocytosis. Mechanistically, glucose uptake via GLUT (glucose transporter)-1 and enhanced glycolysis in neutrophils promoted the production of S100A8/A9. Myeloid-restricted deletion of Slc2a1 (GLUT-1) or pharmacological inhibition of S100A8/A9 reduced TIH-induced myelopoiesis and atherosclerosis. CONCLUSIONS: Together, these data provide a mechanism as to how TIH, prevalent in people with impaired glucose metabolism, contributes to cardiovascular disease. These findings provide a rationale for continual glucose control in these patients and may also suggest that strategies aimed at targeting the S100A8/A9-RAGE (receptor for advanced glycation end products) axis could represent a viable approach to protect the vulnerable blood vessels in diabetes mellitus. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Aterosclerose/etiologia , Glicemia/metabolismo , Hiperglicemia/complicações , Monócitos/metabolismo , Mielopoese , Neutrófilos/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Biomarcadores/sangue , Calgranulina A/genética , Calgranulina A/metabolismo , Calgranulina B/genética , Calgranulina B/metabolismo , Dieta Hiperlipídica , Modelos Animais de Doenças , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Hiperglicemia/sangue , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Monócitos/patologia , Neutrófilos/patologia , Placa Aterosclerótica , Receptor para Produtos Finais de Glicação Avançada/genética , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais
5.
Circulation ; 141(13): 1080-1094, 2020 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-31941367

RESUMO

BACKGROUND: Myocardial infarction (MI) triggers myelopoiesis, resulting in heightened production of neutrophils. However, the mechanisms that sustain their production and recruitment to the injured heart are unclear. METHODS: Using a mouse model of the permanent ligation of the left anterior descending artery and flow cytometry, we first characterized the temporal and spatial effects of MI on different myeloid cell types. We next performed global transcriptome analysis of different cardiac cell types within the infarct to identify the drivers of the acute inflammatory response and the underlying signaling pathways. Using a combination of genetic and pharmacological strategies, we identified the sequelae of events that led to MI-induced myelopoiesis. Cardiac function was assessed by echocardiography. The association of early indexes of neutrophilia with major adverse cardiovascular events was studied in a cohort of patients with acute MI. RESULTS: Induction of MI results in rapid recruitment of neutrophils to the infarct, where they release specific alarmins, S100A8 and S100A9. These alarmins bind to the Toll-like receptor 4 and prime the nod-like receptor family pyrin domain-containing 3 inflammasome in naïve neutrophils and promote interleukin-1ß secretion. The released interleukin-1ß interacts with its receptor (interleukin 1 receptor type 1) on hematopoietic stem and progenitor cells in the bone marrow and stimulates granulopoiesis in a cell-autonomous manner. Genetic or pharmacological strategies aimed at disruption of S100A8/A9 and their downstream signaling cascade suppress MI-induced granulopoiesis and improve cardiac function. Furthermore, in patients with acute coronary syndrome, higher neutrophil count on admission and after revascularization correlates positively with major adverse cardiovascular disease outcomes. CONCLUSIONS: Our study provides novel evidence for the primary role of neutrophil-derived alarmins (S100A8/A9) in dictating the nature of the ensuing inflammatory response after myocardial injury. Therapeutic strategies aimed at disruption of S100A8/A9 signaling or their downstream mediators (eg, nod-like receptor family pyrin domain-containing 3 inflammasome, interleukin-1ß) in neutrophils suppress granulopoiesis and may improve cardiac function in patients with acute coronary syndrome.


Assuntos
Calgranulina A/metabolismo , Granulócitos/metabolismo , Infarto do Miocárdio/sangue , Neutrófilos/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos
6.
Front Immunol ; 10: 2054, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31555280

RESUMO

Monocytes in humans consist of 3 subsets; CD14+CD16- (classical), CD14+CD16+ (intermediate) and CD14dimCD16+ (non-classical), which exhibit distinct and heterogeneous responses to activation. During acute inflammation CD14+CD16- monocytes are significantly elevated and migrate to the sites of injury via the adhesion cascade. The field of immunometabolism has begun to elucidate the importance of the engagement of specific metabolic pathways in immune cell function. Yet, little is known about monocyte metabolism and the role of metabolism in mediating monocyte activation and adherence to vessels. Accordingly, we aimed to determine whether manipulating the metabolism of CD14+CD16- monocytes alters their ability to become activated and adhere. We discovered that LPS stimulation increased the rate of glycolysis in human CD14+CD16- monocytes. Inhibition of glycolysis with 2-deoxy-D-glucose blunted LPS-induced activation and adhesion of monocytes. Mechanistically, we found that increased glycolysis was regulated by mTOR-induced glucose transporter (GLUT)-1. Furthermore, enhanced glycolysis increased accumulation of reactive oxygen species (ROS) and activation of p38 MAPK, which lead to activation and adhesion of monocytes. These findings reveal that glycolytic metabolism is critical for the activation of CD14+CD16- monocytes and contributes to our understanding of the interplay between metabolic substrate preference and immune cell function.


Assuntos
Inflamação/imunologia , Monócitos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adesão Celular , Células Cultivadas , Desoxiglucose/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Glicólise , Humanos , Imunofenotipagem , Receptores de Lipopolissacarídeos/metabolismo , Lipopolissacarídeos/metabolismo , Sistema de Sinalização das MAP Quinases , Monócitos/imunologia , Receptores de IgG/metabolismo , Serina-Treonina Quinases TOR/metabolismo
7.
Haematologica ; 104(3): 456-467, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30361420

RESUMO

Hypertension is a major, independent risk factor for atherosclerotic cardiovascular disease. However, this pathology can arise through multiple pathways, which could influence vascular disease through distinct mechanisms. An overactive sympathetic nervous system is a dominant pathway that can precipitate in elevated blood pressure. We aimed to determine how the sympathetic nervous system directly promotes atherosclerosis in the setting of hypertension. We used a mouse model of sympathetic nervous system-driven hypertension on the atherosclerotic-prone apolipoprotein E-deficient background. When mice were placed on a western type diet for 16 weeks, we showed the evolution of unstable atherosclerotic lesions. Fortuitously, the changes in lesion composition were independent of endothelial dysfunction, allowing for the discovery of alternative mechanisms. With the use of flow cytometry and bone marrow imaging, we found that sympathetic activation caused deterioration of the hematopoietic stem and progenitor cell niche in the bone marrow, promoting the liberation of these cells into the circulation and extramedullary hematopoiesis in the spleen. Specifically, sympathetic activation reduced the abundance of key hematopoietic stem and progenitor cell niche cells, sinusoidal endothelial cells and osteoblasts. Additionally, sympathetic bone marrow activity prompted neutrophils to secrete proteases to cleave the hematopoietic stem and progenitor cell surface receptor CXCR4. All these effects could be reversed using the ß-blocker propranolol during the feeding period. These findings suggest that elevated blood pressure driven by the sympathetic nervous system can influence mechanisms that modulate the hematopoietic system to promote atherosclerosis and contribute to cardiovascular events.


Assuntos
Aterosclerose/sangue , Aterosclerose/etiologia , Hematopoese , Hipertensão/complicações , Hipertensão/etiologia , Sistema Nervoso Simpático/fisiopatologia , Animais , Aterosclerose/patologia , Bloqueio Nervoso Autônomo , Biomarcadores , Biópsia , Medula Óssea/metabolismo , Medula Óssea/patologia , Modelos Animais de Doenças , Suscetibilidade a Doenças , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Mielopoese , Fenótipo , Transdução de Sinais/efeitos dos fármacos , Nicho de Células-Tronco
8.
Cardiovasc Res ; 115(2): 277-291, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590405

RESUMO

Haematopoiesis, the process of blood production, can be altered during the initiation or progression of many diseases. Cardiovascular disease (CVD) has been shown to be heavily influenced by changes to the haematopoietic system, including the types and abundance of immune cells produced. It is now well established that innate immune cells are increased in people with CVD, and the mechanisms contributing to this can be vastly different depending on the risk factors or comorbidities present. Many of these changes begin at the level of the haematopoietic stem and progenitor cells (HSPCs) that reside in the bone marrow (BM). In general, the HSPCs and downstream myeloid progenitors are expanded via increased proliferation in the setting of atherosclerotic CVD. However, HSPCs can also be encouraged to leave the BM and colonise extramedullary sites (i.e. the spleen). Within the BM, HSPCs reside in specialized microenvironments, often referred to as a niche. To date in depth studies assessing the damage or dysregulation that occurs in the BM niche in varying CVDs are scarce. In this review, we provide a general overview of the complex components and interactions within the BM niche and how they influence the function of HSPCs. Additionally, we discuss the main findings regarding changes in the HSPC niche that influence the progression of CVD. We hypothesize that understanding the influence of the BM niche in CVD will aid in delineating new pathways for therapeutic interventions.


Assuntos
Aterosclerose/metabolismo , Sistema Cardiovascular/metabolismo , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Nicho de Células-Tronco , Animais , Aterosclerose/patologia , Aterosclerose/fisiopatologia , Sistema Cardiovascular/patologia , Sistema Cardiovascular/fisiopatologia , Progressão da Doença , Células-Tronco Hematopoéticas/patologia , Humanos , Fenótipo , Placa Aterosclerótica , Transdução de Sinais
9.
Eur Heart J ; 39(23): 2158-2167, 2018 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-29905812

RESUMO

Aim: Rheumatoid arthritis (RA) is associated with an approximately two-fold elevated risk of cardiovascular (CV)-related mortality. Patients with RA present with systemic inflammation including raised circulating myeloid cells, but fail to display traditional CV risk-factors, particularly dyslipidaemia. We aimed to explore if increased circulating myeloid cells is associated with impaired atherosclerotic lesion regression or altered progression in RA. Methods and results: Using flow cytometry, we noted prominent monocytosis, neutrophilia, and thrombocytosis in two mouse models of RA. This was due to enhanced proliferation of the haematopoietic stem and progenitor cells (HSPCs) in the bone marrow and the spleen. HSPCs expansion was associated with an increase in the cholesterol content, due to a down-regulation of cholesterol efflux genes, Apoe, Abca1, and Abcg1. The HSPCs also had enhanced expression of key myeloid promoting growth factor receptors. Systemic inflammation was found to cause defective cellular cholesterol metabolism. Increased myeloid cells in mice with RA were associated with a significant impairment in lesion regression, even though cholesterol levels were equivalent to non-arthritic mice. Lesions from arthritic mice exhibited a less stable phenotype as demonstrated by increased immune cell infiltration, lipid accumulation, and decreased collagen formation. In a progression model, we noted monocytosis, enhanced monocytes recruitment to lesions, and increased plaque macrophages. This was reversed with administration of reconstituted high-density lipoprotein (rHDL). Furthermore, RA patients have expanded CD16+ monocyte subsets and a down-regulation of ABCA1 and ABCG1. Conclusion: Rheumatoid arthritis impairs atherosclerotic regression and alters progression, which is associated with an expansion of myeloid cells and disturbed cellular cholesterol handling, independent of plasma cholesterol levels. Infusion of rHDL prevented enhanced myelopoiesis and monocyte entry into lesions. Targeting cellular cholesterol defects in people with RA, even if plasma cholesterol is within the normal range, may limit vascular disease.


Assuntos
Artrite Reumatoide/metabolismo , Aterosclerose/metabolismo , Colesterol/metabolismo , Células-Tronco Hematopoéticas/metabolismo , Monócitos/metabolismo , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adulto , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Artrite Reumatoide/imunologia , Aterosclerose/genética , Aterosclerose/imunologia , Modelos Animais de Doenças , Regulação para Baixo , Feminino , Hematopoese Extramedular/imunologia , Humanos , Leucocitose , Receptores X do Fígado/genética , Receptores X do Fígado/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Monócitos/imunologia , Mielopoese/imunologia , Neutrófilos , RNA Mensageiro/metabolismo , Trombocitose
11.
Curr Opin Lipidol ; 29(3): 240-245, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29528857

RESUMO

PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) reside in the bone marrow and are important in replenishing all cells in the blood through a process termed hematopoiesis. One of the defining characteristics of HSCs is that they must be able to balance their self-renewal capacity with their differentiation into committed blood cells in various blood lineages. For these events to occur, HSCs must be tightly regulated in the bone marrow by intrinsic and extrinsic factors to maintain steady hematopoiesis. RECENT FINDINGS: Recently, the effect on how metabolism regulates HSC function has received a great amount of attention. In particular, lipids have been found to participate in mitochondrial activity to maintain HSCs, a role previously overlooked due to HSCs being thought of as mostly glycolytic. Moreover, there has been a re-emergence of how adipocytes in the bone marrow can regulate HSCs. SUMMARY: As these areas evolve, more studies are required to determine the exact contribution of lipids toward HSC maintenance. These studies will allow newer therapeutic targets to help reduce abnormal hematopoiesis such as myelopoiesis, which contributes to many metabolic diseases.


Assuntos
Medula Óssea/metabolismo , Glicólise/fisiologia , Hematopoese/fisiologia , Células-Tronco Hematopoéticas/metabolismo , Metabolismo dos Lipídeos/fisiologia , Adipócitos/citologia , Adipócitos/metabolismo , Animais , Células-Tronco Hematopoéticas/citologia , Humanos
12.
Atherosclerosis ; 271: 166-176, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29518749

RESUMO

BACKGROUND AND AIMS: Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia. METHODS: Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout (Ldlr-/-) mice after which they were fed a high-cholesterol diet for 4 weeks. Control and diabetic mice were treated with vehicle or sodium glucose cotransporter inhibitor (SGLT2i, Phlorizin or Dapagliflozin) for the duration of the diet. RESULTS: Induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. These mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Tighter glycemic control by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver. Further examination of the liver revealed an important role for bile acid transporters (Abcg5, Abcg8) and cytochrome P450 enzymes in the clearance of hepatic cholesterol. CONCLUSIONS: These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance exclusive of Ldlr, likely via HSPG and bile acid pathways, and has an overall net positive effect on atherosclerosis.


Assuntos
Aterosclerose/prevenção & controle , Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Glucosídeos/farmacologia , Hiperlipidemias/tratamento farmacológico , Lipoproteínas/sangue , Florizina/farmacologia , Receptores de LDL/deficiência , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Membro 5 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Membro 8 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Colesterol na Dieta , Sistema Enzimático do Citocromo P-450/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/induzido quimicamente , Heparina/análogos & derivados , Heparina/metabolismo , Hiperlipidemias/sangue , Hiperlipidemias/genética , Lipoproteínas/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Proteoglicanas/metabolismo , Receptores de LDL/genética , Estreptozocina
13.
Haematologica ; 103(4): 597-606, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29371326

RESUMO

Obesity enhances the risk of developing myelodysplastic syndromes. However, the effect of obesity on survival is unclear. Obese people present with monocytosis due to inflammatory signals emanating from obese adipose tissue. We hypothesized that obesity-induced myelopoiesis would promote the transition of myelodysplastic syndrome to acute myeloid leukemia and accelerate mortality in obesity. Obese Ob/Ob mice or their lean littermate controls received a bone marrow transplant from NUP98-HOXD13 transgenic mice, a model of myelodysplastic syndrome. The metabolic parameters of the mice were examined throughout the course of the study, as were blood leukocytes. Myeloid cells were analyzed in the bone, spleen, liver and adipose tissue by flow cytometry halfway through the disease progression and at the endpoint. Survival curves were also calculated. Contrary to our hypothesis, transplantation of NUP98-HOXD13 bone marrow into obese recipient mice significantly increased survival time compared with lean recipient controls. While monocyte skewing was exacerbated in obese mice receiving NUP98-HOXD13 bone marrow, transformation to acute myeloid leukemia was not enhanced. Increased survival of obese mice was associated with a preservation of fat mass as well as increased myeloid cell deposition within the adipose tissue, and a concomitant reduction in detrimental myeloid cell accumulation within other organs. The study herein revealed that obesity increases survival in animals with myelodysplastic syndrome. This may be due to the greater fat mass of Ob/Ob mice, which acts as a sink for myeloid cells, preventing their accumulation in other key organs, such as the liver.


Assuntos
Síndromes Mielodisplásicas/mortalidade , Obesidade , Animais , Medula Óssea/química , Transplante de Medula Óssea , Modelos Animais de Doenças , Proteínas de Homeodomínio , Leptina/deficiência , Leucemia Mieloide Aguda/etiologia , Camundongos , Camundongos Transgênicos , Síndromes Mielodisplásicas/patologia , Células Mieloides , Complexo de Proteínas Formadoras de Poros Nucleares , Taxa de Sobrevida , Fatores de Transcrição
14.
Sci Rep ; 7(1): 16615, 2017 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-29192208

RESUMO

Endogenous anti-inflammatory annexin-A1 (ANX-A1) plays an important role in preserving left ventricular (LV) viability and function after ischaemic insults in vitro, but its long-term cardioprotective actions in vivo are largely unknown. We tested the hypothesis that ANX-A1-deficiency exaggerates inflammation, haematopoietic stem progenitor cell (HSPC) activity and LV remodelling in response to myocardial ischaemia in vivo. Adult ANX - A1 -/- mice subjected to coronary artery occlusion exhibited increased infarct size and LV macrophage content after 24-48 h reperfusion compared with wildtype (WT) counterparts. In addition, ANX - A1 -/- mice exhibited greater expansion of HSPCs and altered pattern of HSPC mobilisation 8 days post-myocardial infarction, with increased circulating neutrophils and platelets, consistent with increased cardiac inflammation as a result of increased myeloid invading injured myocardium in response to MI. Furthermore, ANX - A1 -/- mice exhibited significantly increased expression of LV pro-inflammatory and pro-fibrotic genes and collagen deposition after MI compared to WT counterparts. ANX-A1-deficiency increased cardiac necrosis, inflammation, hypertrophy and fibrosis following MI, accompanied by exaggerated HSPC activity and impaired macrophage phenotype. These findings suggest that endogenous ANX-A1 regulates mobilisation and differentiation of HSPCs. Limiting excessive monocyte/neutrophil production may limit LV damage in vivo. Our findings support further development of novel ANX-A1-based therapies to improve cardiac outcomes after MI.


Assuntos
Anexina A1/genética , Mobilização de Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/metabolismo , Infarto do Miocárdio/metabolismo , Miocardite/etiologia , Animais , Anexina A1/metabolismo , Modelos Animais de Doenças , Células-Tronco Hematopoéticas/citologia , Macrófagos/imunologia , Macrófagos/metabolismo , Macrófagos/patologia , Masculino , Camundongos , Camundongos Knockout , Infarto do Miocárdio/complicações , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/patologia , Isquemia Miocárdica/complicações , Isquemia Miocárdica/genética , Miocardite/metabolismo , Miocardite/patologia , Necrose , Ratos
15.
Atherosclerosis ; 265: 47-53, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28858686

RESUMO

BACKGROUND AND AIMS: Monocyte levels predict cardiovascular outcomes and play a causal role in atherogenesis. Monocytes can be produced in the spleen and track to the atherosclerotic lesion in significant numbers. The cholinergic system has been shown to have anti-inflammatory actions in the spleen. We aimed to explore whether therapeutic stimulation of the nicotinic acetylcholine receptor alpha 7 (nAChRα7) can suppress atherogenesis. METHODS: Apoe-/- mice were placed on a Western-type diet and treated with bi-daily injections of the nAChRα7 agonist GTS-21 or vehicle every 2-3 days for 8 weeks. RESULTS: GTS-21 caused a reduction in atherosclerosis in the aortic arch and proximal aorta. This also resulted in less plaque macrophages. Moreover, GTS-21 reduced the abundance of blood monocytes, which was caused by inhibition of inflammatory cytokines and extramedullary hematopoiesis in the spleen, along with splenic monocytes. CONCLUSIONS: Stimulation of nAChRα7 with GTS-21 reduced atherosclerosis, which was associated with dampened splenic myelopoiesis.


Assuntos
Aorta Torácica/efeitos dos fármacos , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Compostos de Benzilideno/farmacologia , Mielopoese/efeitos dos fármacos , Agonistas Nicotínicos/farmacologia , Piridinas/farmacologia , Baço/efeitos dos fármacos , Receptor Nicotínico de Acetilcolina alfa7/agonistas , Animais , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Doenças da Aorta/genética , Doenças da Aorta/metabolismo , Doenças da Aorta/patologia , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Dieta Ocidental , Modelos Animais de Doenças , Masculino , Camundongos Knockout para ApoE , Placa Aterosclerótica , Baço/metabolismo , Receptor Nicotínico de Acetilcolina alfa7/metabolismo
16.
J Clin Invest ; 127(6): 2133-2147, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28504650

RESUMO

Platelets play a critical role in atherogenesis and thrombosis-mediated myocardial ischemia, processes that are accelerated in diabetes. Whether hyperglycemia promotes platelet production and whether enhanced platelet production contributes to enhanced atherothrombosis remains unknown. Here we found that in response to hyperglycemia, neutrophil-derived S100 calcium-binding proteins A8/A9 (S100A8/A9) interact with the receptor for advanced glycation end products (RAGE) on hepatic Kupffer cells, resulting in increased production of IL-6, a pleiotropic cytokine that is implicated in inflammatory thrombocytosis. IL-6 acts on hepatocytes to enhance the production of thrombopoietin, which in turn interacts with its cognate receptor c-MPL on megakaryocytes and bone marrow progenitor cells to promote their expansion and proliferation, resulting in reticulated thrombocytosis. Lowering blood glucose using a sodium-glucose cotransporter 2 inhibitor (dapagliflozin), depleting neutrophils or Kupffer cells, or inhibiting S100A8/A9 binding to RAGE (using paquinimod), all reduced diabetes-induced thrombocytosis. Inhibiting S100A8/A9 also decreased atherogenesis in diabetic mice. Finally, we found that patients with type 2 diabetes have reticulated thrombocytosis that correlates with glycated hemoglobin as well as increased plasma S100A8/A9 levels. These studies provide insights into the mechanisms that regulate platelet production and may aid in the development of strategies to improve on current antiplatelet therapies and to reduce cardiovascular disease risk in diabetes.


Assuntos
Aterosclerose/imunologia , Calgranulina A/fisiologia , Calgranulina B/fisiologia , Diabetes Mellitus Experimental/imunologia , Neutrófilos/metabolismo , Trombocitose/imunologia , Animais , Aterosclerose/metabolismo , Plaquetas/fisiologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Obesos , Trombocitose/metabolismo
17.
Cardiovasc Drugs Ther ; 31(2): 145-156, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28204966

RESUMO

PURPOSE: Inhibition of the renin-angiotensin system (RAS) is beneficial in patient management after myocardial infarction (MI). However, whether RAS inhibition also provides cardiac protection in the acute phase of MI is unclear. METHODS: Male 129sv mice underwent coronary artery occlusion to induce MI, followed by treatment with losartan (L, 20 and 60 mg/kg), perindopril (P, 2 and 6 mg/kg), amlodipine (20 mg/kg as a BP-lowering agent) or vehicle as control. Drug effects on hemodynamics were examined. Effects of treatments on incidence of cardiac rupture, haematological profile, monocyte and neutrophil population in the spleen and the heart, cardiac leukocyte density, expression of inflammatory genes and activity of MMPs were studied after MI. RESULTS: Incidence of cardiac rupture within 2 weeks was significantly and similarly reduced by both losartan (L) and perindopril (P) in a dose-dependent manner [75% (27/36) in vehicle, 40-45% in low-dose (L 10/22, P 8/20) and 16-20% (L 5/32, P 4/20) in high-dose groups, all P < 0.05]. This action was independent of their BP-lowering action, as amlodipine reduced BP to a similar degree without effect on rupture (70%, 21/30). Compared to the control group, high dose losartan and perindopril decreased counts of white blood cells, neutrophils and lymphocytes (all P < 0.05), and inhibited splenic monocyte and neutrophil release into the circulation. Consequently, monocyte, neutrophil and leukocyte infiltration, inflammatory gene expressions (IL-1ß, IL-6, MMP9, MCP-1, TNF-α and TGFß1) and activity of MMP2 and MMP9 in the infarct tissue were attenuated by losartan and/or perindopril treatment (all P < 0.05). CONCLUSIONS: RAS inhibition by losartan or perindopril prevented cardiac rupture at the acute phase of MI through blockade of splenic release of monocytes and neutrophils and consequently attenuation of systemic and regional inflammatory responses.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Anti-Inflamatórios/farmacologia , Ruptura Cardíaca Pós-Infarto/prevenção & controle , Inflamação/prevenção & controle , Losartan/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/metabolismo , Perindopril/farmacologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Anlodipino/farmacologia , Animais , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ruptura Cardíaca Pós-Infarto/etiologia , Ruptura Cardíaca Pós-Infarto/metabolismo , Ruptura Cardíaca Pós-Infarto/patologia , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Masculino , Camundongos da Linhagem 129 , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/patologia , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Baço/efeitos dos fármacos , Baço/metabolismo , Fatores de Tempo
18.
Thromb Haemost ; 115(4): 762-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26676845

RESUMO

Recruitment of monocytes in atherosclerosis is dependent upon increased levels of plasma lipoproteins which accumulate in the blood vessel wall. The extracellular milieu can influence the phenotype of monocyte subsets (classical: CD14++CD16-, intermediate: CD14+CD16+ and non-classical: CD14dimCD16++) and macrophages (M1 or M2) and consequently the initiation, progression and/or regression of atherosclerosis. However, it is not known what effect lipoproteins, in particular native low-density lipoproteins (nLDL), have on the polarisation of monocyte-derived macrophages. Monocytes were differentiated into macrophages in the presence of nLDL. nLDL increased gene expression of the inflammatory cytokines TNFα and IL-6 in macrophages polarised towards the M1 phenotype while decreasing the M2 surface markers, CD206 and CD200R and the anti-inflammatory cytokines TGFß and IL-10. Compared to the classical and intermediate subsets, the non-classical subset-derived macrophages had a reduced ability to respond to M1 stimuli (LPS and IFNγ). nLDL enhanced the TNFα and IL-6 gene expression in macrophages from all monocyte subsets, indicating an inflammatory effect of nLDL. Further, the classical and intermediate subsets both responded to M2 stimuli (IL-4) with upregulation of TGFß and SR-B1 mRNA; an effect, which was reduced by nLDL. In contrast, the non-classical subset failed to respond to IL-4 or nLDL, suggesting it may be unable to polarise into M2 macrophages. Our data suggests that monocyte interaction with nLDL significantly affects macrophage polarisation and that this interaction appears to be subset dependent.


Assuntos
Aterosclerose/metabolismo , Diferenciação Celular , Lipoproteínas LDL/metabolismo , Macrófagos/fisiologia , Monócitos/fisiologia , Antígenos CD/metabolismo , Aterosclerose/patologia , Células Cultivadas , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fenótipo , Receptores Depuradores Classe B/genética , Receptores Depuradores Classe B/metabolismo
19.
Br J Pharmacol ; 173(4): 741-51, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26332942

RESUMO

BACKGROUND AND PURPOSE: Monocyte-derived macrophages are critical in the development of atherosclerosis and can adopt a wide range of functional phenotypes depending on their surrounding milieu. High-density lipoproteins (HDLs) have many cardio-protective properties including potent anti-inflammatory effects. We investigated the effects of HDL on human macrophage phenotype and the mechanisms by which these occur. EXPERIMENTAL APPROACH: Human blood monocytes were differentiated into macrophages in the presence or absence of HDL and were then induced to either an inflammatory macrophage (M1) or anti-inflammatory macrophage (M2) phenotype using LPS and IFN-γ or IL-4, respectively. KEY RESULTS: HDL inhibited the induction of macrophages to an M1-phenotype, as evidenced by a decrease in the expression of M1-specific cell surface markers CD192 and CD64, as well as M1-associated inflammatory genes TNF-α, IL-6 and MCP-1 (CCL2). HDL also inhibited M1 function by reducing the production of ROS. In contrast, HDL had no effect on macrophage induction to the M2-phenotype. Similarly, methyl-ß-cyclodextrin, a non-specific cholesterol acceptor also suppressed the induction of M1 suggesting that cholesterol efflux is important in this process. Furthermore, HDL decreased membrane caveolin-1 in M1 macrophages. We confirmed that caveolin-1 is required for HDL to inhibit M1 induction as bone marrow-derived macrophages from caveolin-1 knockout mice continued to polarize into M1-phenotype despite the presence of HDL. Moreover, HDL decreased ERK1/2 and STAT3 phosphorylation in M1 macrophages. CONCLUSIONS AND IMPLICATIONS: We concluded that HDL reduces the induction of macrophages to the inflammatory M1-phenotype via redistribution of caveolin-1, preventing the activation of ERK1/2 and STAT3.


Assuntos
Caveolina 1/metabolismo , Lipoproteínas HDL/farmacologia , Macrófagos/citologia , Macrófagos/efeitos dos fármacos , Animais , Caveolina 1/deficiência , Humanos , Lipoproteínas HDL/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Knockout , Fenótipo , Espécies Reativas de Oxigênio/metabolismo
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