RESUMO
AIMS: Monocytes play critical roles in tissue injury and repair following acute myocardial infarction (AMI). Specifically targeting inflammatory monocytes in experimental models leads to reduced infarct size and improved healing. However, data from humans are sparse, and it remains unclear whether monocytes play an equally important role in humans. The aim of this study was to investigate whether the monocyte response following AMI is conserved between humans and mice and interrogate patterns of gene expression to identify regulated functions. METHODS AND RESULTS: Thirty patients (AMI) and 24 control patients (stable coronary atherosclerosis) were enrolled. Female C57BL/6J mice (n = 6/group) underwent AMI by surgical coronary ligation. Myocardial injury was quantified by magnetic resonance imaging (human) and echocardiography (mice). Peripheral monocytes were isolated at presentation and at 48 h. RNA from separated monocytes was hybridized to Illumina beadchips. Acute myocardial infarction resulted in a significant peripheral monocytosis in both species that positively correlated with the extent of myocardial injury. Analysis of the monocyte transcriptome following AMI demonstrated significant conservation and identified inflammation and mitosis as central processes to this response. These findings were validated in both species. CONCLUSIONS: Our findings show that the monocyte transcriptome is conserved between mice and humans following AMI. Patterns of gene expression associated with inflammation and proliferation appear to be switched on prior to their infiltration of injured myocardium suggesting that the specific targeting of inflammatory and proliferative processes in these immune cells in humans are possible therapeutic strategies. Importantly, they could be effective in the hours after AMI.
Assuntos
Leucócitos Mononucleares/patologia , Infarto do Miocárdio/patologia , Idoso , Animais , Estudos de Casos e Controles , Proliferação de Células/fisiologia , Feminino , Perfilação da Expressão Gênica , Humanos , Inflamação/imunologia , Inflamação/patologia , Leucócitos Mononucleares/imunologia , Ligadura , Angiografia por Ressonância Magnética , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Infarto do Miocárdio/genética , Infarto do Miocárdio/imunologia , Fenótipo , Transcrição Gênica/genética , Transcrição Gênica/imunologia , Ativação Transcricional/fisiologiaRESUMO
OBJECTIVE: To explore the role of systemic inflammation in the regulation of adiponectin levels in patients with ischemic heart disease. APPROACH AND RESULTS: In a cross-sectional study of 575 subjects, serum adiponectin was compared between healthy subjects, patients with coronary artery disease with no/mild/severe heart failure (HF), and patients with nonischemic HF. Adiponectin expression and release from femoral, subcutaneous and thoracic adipose tissue was determined in 258 additional patients with coronary artery bypass grafting. Responsiveness of the various human adipose tissue depots to interleukin-6, tumor necrosis factor-α, and brain natriuretic peptide (BNP) was examined by using ex vivo models of human fat. The effects of inducible low-grade inflammation were tested by using the model of Salmonella typhi vaccine-induced inflammation in healthy individuals. In the cross-sectional study, HF strikingly increased adiponectin levels. Plasma BNP was the strongest predictor of circulating adiponectin and its release from all adipose tissue depots in patients with coronary artery bypass grafting, even in the absence of HF. Femoral AT was the depot with the least macrophages infiltration and the largest adipocyte cell size and the only responsive to systemic and ex vivo proinflammatory stimulation (effect reversible by BNP). Low-grade inflammation reduced circulating adiponectin levels, while circulating BNP remained unchanged. CONCLUSIONS: This study demonstrates the regional variability in the responsiveness of human adipose tissue to systemic inflammation and suggests that BNP (not systemic inflammation) is the main driver of circulating adiponectin in patients with advanced atherosclerosis even in the absence of HF. Any interpretation of circulating adiponectin as a biomarker should take into account the underlying disease state, background inflammation, and BNP levels.
Assuntos
Adiponectina/biossíntese , Tecido Adiposo/metabolismo , Insuficiência Cardíaca/metabolismo , Inflamação/metabolismo , Isquemia Miocárdica/metabolismo , Peptídeo Natriurético Encefálico/fisiologia , Adiponectina/genética , Idoso , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/fisiopatologia , Ponte de Artéria Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/metabolismo , Estudos Transversais , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Interleucina-6/sangue , Interleucina-6/farmacologia , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/complicações , Peptídeo Natriurético Encefálico/sangue , Técnicas de Cultura de Órgãos , Especificidade de Órgãos , Fatores de Risco , Gordura Subcutânea , Coxa da Perna , Tórax , Fator de Necrose Tumoral alfa/farmacologia , Ultrassonografia , Vasodilatação , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
BACKGROUND: Adiponectin is an adipokine with potentially important roles in human cardiovascular disease states. We studied the role of adiponectin in the cross-talk between adipose tissue and vascular redox state in patients with atherosclerosis. METHODS AND RESULTS: The study included 677 patients undergoing coronary artery bypass graft surgery. Endothelial function was evaluated by flow-mediated dilation of the brachial artery in vivo and by vasomotor studies in saphenous vein segments ex vivo. Vascular superoxide (O2(-)) and endothelial nitric oxide synthase (eNOS) uncoupling were quantified in saphenous vein and internal mammary artery segments. Local adiponectin gene expression and ex vivo release were quantified in perivascular (saphenous vein and internal mammary artery) subcutaneous and mesothoracic adipose tissue from 248 patients. Circulating adiponectin was independently associated with nitric oxide bioavailability and O2(-) production/eNOS uncoupling in both arteries and veins. These findings were supported by a similar association between functional polymorphisms in the adiponectin gene and vascular redox state. In contrast, local adiponectin gene expression/release in perivascular adipose tissue was positively correlated with O2(-) and eNOS uncoupling in the underlying vessels. In ex vivo experiments with human saphenous veins and internal mammary arteries, adiponectin induced Akt-mediated eNOS phosphorylation and increased tetrahydrobiopterin bioavailability, improving eNOS coupling. In ex vivo experiments with human saphenous veins/internal mammary arteries and adipose tissue, we demonstrated that peroxidation products produced in the vascular wall (ie, 4-hydroxynonenal) upregulate adiponectin gene expression in perivascular adipose tissue via a peroxisome proliferator-activated receptor-γ-dependent mechanism. CONCLUSIONS: We demonstrate for the first time that adiponectin improves the redox state in human vessels by restoring eNOS coupling, and we identify a novel role of vascular oxidative stress in the regulation of adiponectin expression in human perivascular adipose tissue.
Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Doença da Artéria Coronariana/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Adiponectina/genética , Idoso , Aldeídos/metabolismo , Ponte de Artéria Coronária , Doença da Artéria Coronariana/cirurgia , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Artéria Torácica Interna/metabolismo , Artéria Torácica Interna/transplante , Óxido Nítrico/metabolismo , Oxirredução , Estresse Oxidativo/fisiologia , PPAR gama/metabolismo , Veia Safena/metabolismo , Veia Safena/transplante , Superóxidos/metabolismo , Vasodilatação/fisiologiaRESUMO
AIM: Acute injury and subsequent remodelling responses to ST-segment elevation myocardial infarction (STEMI) are major determinants of clinical outcome. Current imaging and plasma biomarkers provide delayed readouts of myocardial injury and recovery. Here, we sought to systematically characterize all microRNAs (miRs) released during the acute phase of STEMI and relate miR release to magnetic resonance imaging (MRI) findings to predict acute and late responses to STEMI, from a single early blood sample. METHODS AND RESULTS: miRs were quantified in blood samples obtained from patients after primary PCI (PPCI) for STEMI. Cardiac MRI (cMRI) was performed to quantify myocardial edema, infarct size and salvage index. Regression models were constructed to predict these outcomes measures, which were then tested with a validation cohort. Transcoronary miR release was quantified from paired measurements of coronary artery and coronary sinus samples. A cell culture model was used to identify endothelial cell-derived miRs.A total of 72 patients undergoing PPCI for acute STEMI underwent miR analysis and cMRI. About >200 miRs were detectable in plasma after STEMI, from which 128 miRs were selected for quantification in all patients. Known myocardial miRs demonstrated a linear correlation with troponin release, and these increased across the transcoronary gradient. We identified novel miRs associated with microvascular injury and myocardial salvage. Regression models were constructed using a training cohort, then tested in a validation cohort, and predicted myocardial oedema, infarct size and salvage index. CONCLUSION: Analysis of miR release after STEMI identifies biomarkers that predict both acute and late outcomes after STEMI. A novel miR-based biomarker score enables the estimation of area at risk, late infarct size and salvage index from a single blood sample 6 hours after PPCI, providing a simple and rapid alternative to serial cMRI characterization of STEMI outcome.
Assuntos
Infarto Miocárdico de Parede Anterior , MicroRNAs , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST , Humanos , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Intervenção Coronária Percutânea/métodos , Infarto Miocárdico de Parede Anterior/complicações , MicroRNAs/genética , Biomarcadores , Células Endoteliais , Resultado do TratamentoRESUMO
GPR109A has generated expanding interest since its discovery as the receptor for niacin a decade ago, along with deorphanisation as the receptor for endogenous ligand 3-hydroxy-butyrate shortly after. This interest is generated especially because of the continuing exploration of niacin's "pleiotropic" mechanisms of action and its potential in the "cross-talk" between metabolic and inflammatory pathways. As GPR109A's primary pharmacological ligand in clinical use, niacin has been used for over 50 years in the treatment of cardiovascular disease, mainly due to its favourable effects on plasma lipoproteins. However, it has become apparent that niacin also possesses lipoprotein-independent effects that influence inflammatory pathways mediated through GPR109A. In addition to its G-protein-mediated effects, recent evidence has emerged to support alternative GPR109A signalling via adaptive protein ß-arrestins. In this article, we consider the role of GPR109A and its downstream effects in the context of atherosclerosis and vascular inflammation, along with insights into strategy for future drug development.
Assuntos
Aterosclerose/fisiopatologia , Receptores Acoplados a Proteínas G/fisiologia , Receptores Nicotínicos/fisiologia , Vasculite/fisiopatologia , Arrestinas/fisiologia , Aterosclerose/tratamento farmacológico , Aterosclerose/imunologia , Humanos , Hipolipemiantes/uso terapêutico , Lipoproteínas/metabolismo , Niacina/uso terapêutico , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/imunologia , Receptores Nicotínicos/imunologia , Vasculite/tratamento farmacológico , Vasculite/imunologiaRESUMO
RATIONALE AND OBJECTIVE: Acute myocardial infarction (AMI) results in the recruitment of leukocytes to injured myocardium. Additionally, myocardium remote to the infarct zone also becomes inflamed and is associated with adverse left ventricular remodelling. Renal ischaemic syndromes have been associated with remote organ inflammation and impaired function. Here, we tested the hypothesis that AMI results in remote organ (renal) inflammation. METHODS: Mice were subjected to either AMI, sham procedure or no procedure and the inflammatory response in peripheral blood, injured and remote myocardium, and kidneys was studied at 24 h. RESULTS: AMI resulted in increased circulating neutrophils (P < 0.001) and monocytes (P < 0.001). mRNA for inflammatory mediators significantly increased in infarcted myocardium and in remote myocardium. VCAM-1 mRNA was increased in both infarcted and remote myocardium. VCAM-1 protein was also increased in the kidneys of AMI mice (P < 0.05) and immunofluorescence revealed localisation of VCAM-1 to glomeruli, associated with leukocyte infiltration and increased local inflammatory mRNA expression. CONCLUSIONS: We conclude that in addition to local inflammation, AMI results in remote organ inflammation evidenced by (1) increased expression of mRNA for inflammatory cytokines, (2) marked upregulation of VCAM-1 in renal glomeruli, and (3) the recruitment and infiltration of leukocytes in the kidney.
Assuntos
Glomerulonefrite/etiologia , Glomérulos Renais/imunologia , Infarto do Miocárdio/complicações , Miocardite/etiologia , Miocárdio/imunologia , Animais , Citocinas/genética , Feminino , Glomerulonefrite/imunologia , Leucócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/imunologia , Miocardite/imunologia , RNA Mensageiro/metabolismo , Molécula 1 de Adesão de Célula Vascular/genética , Molécula 1 de Adesão de Célula Vascular/imunologiaRESUMO
Niacin has been used for more than 50 years in the treatment of cardiovascular disease, although its use has largely been superseded by better-tolerated lipid-modulating interventions. There has been a renewed interest in the HDL-cholesterol raising properties of niacin, with the appreciation that substantial cardiovascular risk remains despite effective treatment of LDL-cholesterol. This coincides with increasing evidence that the complex functional properties of HDL are not well reflected by measurement of HDL-cholesterol alone. In addition to favorable actions on lipoproteins, it is becoming apparent that niacin may also possess lipoprotein independent or pleiotropic effects including the inhibition of inflammatory pathways mediated by its receptor GPR109A, which is expressed by adipocytes and some leukocytes. In this article we consider emerging and prior clinical trial data relating to niacin. We review recent data in respect of mechanisms of action on lipoproteins, which remain complex and incompletely understood. We discuss the recent reports of anti-inflammatory effects of niacin in adipocytes and through bone marrow derived cells and vascular endothelium. These novel observations come at an interesting time, with current imaging and outcome studies leaving outstanding questions on niacin efficacy in statin-treated patients.
Assuntos
Anti-Inflamatórios/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Niacina/uso terapêutico , Animais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/complicações , Humanos , Resultado do Tratamento , Regulação para CimaRESUMO
OBJECTIVE: Nicotinic acid (NA) treatment has been associated with benefits in atherosclerosis that are usually attributed to effects on plasma lipoproteins. The NA receptor GPR109A is expressed in monocytes and macrophages, suggesting a possible additional role for NA in modulating function of these immune cells. We hypothesize that NA has the potential to act directly on monocytes to alter mediators of inflammation that may contribute to its antiatherogenic effects in vivo. METHODS AND RESULTS: In human monocytes activated by Toll-like receptor (TLR)-4 agonist lipopolysaccharide, NA reduced secretion of proinflammatory mediators: TNF-α (by 49.2±4.5%); interleukin-6 (by 56.2±2.8%), and monocyte chemoattractant protein-1 (by 43.2±3.1%) (P<0.01). In TLR2 agonist, heat-killed Listeria monocytogenes-activated human monocytes, NA reduced secretion of TNF-α (by 48.6±7.1%), interleukin-6 (by 60.9±1.6%), and monocyte chemoattractant protein-1 (by 59.3±5.3%) (P<0.01; n=7). Knockdown of GPR109A by siRNA resulted in a loss of this anti-inflammatory effect in THP-1 monocytes. However, inhibition of prostaglandin D2 receptor by MK0524 or COX2 by NS398 did not alter the anti-inflammatory effects of NA observed in activated human monocytes. Preincubation of THP-1 monocytes with NA 0.1 mmol/L reduced phosphorylated IKKß by 42±2% (P<0.001) IKB-α by 54±14% (P<0.01). Accumulation of nuclear p65 NF-κB in response to lipopolysaccharide treatment was also profoundly inhibited, by 89±1.3% (n=4; P<0.01). NA potently inhibited monocyte adhesion to activated HUVEC, and VCAM, mediated by the integrin, very late antigen 4. Monocyte chemotaxis was also significantly reduced (by 45.7±1.2%; P<0.001). CONCLUSION: NA displays a range of effects that are lipoprotein-independent and potentially antiatherogenic. These effects are mediated by GPR109A and are independent of prostaglandin pathways. They suggest a rationale for treatment with NA that is not dependent on levels of plasma cholesterol and possible applications beyond the treatment of dyslipidemia.
Assuntos
Anti-Inflamatórios/farmacologia , Inflamação/metabolismo , Monócitos/efeitos dos fármacos , Niacina/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Nicotínicos/efeitos dos fármacos , Adesão Celular/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Quinase I-kappa B/metabolismo , Inflamação/genética , Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Integrina alfa4beta1/metabolismo , Interleucina-6/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/imunologia , Monócitos/metabolismo , Fosforilação , Pirazinas/farmacologia , Interferência de RNA , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Receptores Imunológicos/antagonistas & inibidores , Receptores Imunológicos/metabolismo , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Receptores de Prostaglandina/antagonistas & inibidores , Receptores de Prostaglandina/metabolismo , Receptor 2 Toll-Like/agonistas , Receptor 2 Toll-Like/metabolismo , Receptor 4 Toll-Like/agonistas , Receptor 4 Toll-Like/metabolismo , Fator de Transcrição RelA/metabolismo , Transfecção , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
Adiponectin is an abundantly circulating adipokine, orchestrating its effects through two 7-transmembrane receptors (AdipoR1 and AdipoR2). Steroidogenesis is regulated by a variety of neuropeptides and adipokines. Earlier studies have reported adipokine mediated steroid production. A key rate-limiting step in steroidogenesis is cholesterol transportation across the mitochondrial membrane by steroidogenic acute regulatory protein (StAR). Several signalling pathways regulate StAR expression. The actions of adiponectin and its role in human adrenocortical steroid biosynthesis are not fully understood. The aim of this study was to investigate the effects of adiponectin on StAR protein expression, steroidogenic genes, and cortisol production and to dissect the signalling cascades involved in the activation of StAR expression. Using qRT-PCR, Western blot analysis and ELISA, we have demonstrated that stimulation of human adrenocortical H295R cells with adiponectin results in increased cortisol secretion. This effect is accompanied by increased expression of key steroidogenic pathway genes including StAR protein expression via ERK1/2 and AMPK-dependent pathways. This has implications for our understanding of adiponectin receptor activation and peripheral steroidogenesis. Finally, our study aims to emphasise the key role of adipokines in the integration of metabolic activity and energy balance partly via the regulation of adrenal steroid production. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/farmacologia , Córtex Suprarrenal/citologia , Córtex Suprarrenal/enzimologia , Hidrocortisona/biossíntese , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Fosfoproteínas/metabolismo , Adiponectina/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Hidrocortisona/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Fosfoproteínas/genética , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Fatores de Tempo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
AIMS: The endothelium plays a role in regulating vascular tone. Acute and dynamic changes in low-flow-mediated constriction (L-FMC) and how it changes with regard to traditional flow-mediated dilatation (FMD) have not been described. We aimed to investigate the changes in brachial artery L-FMC following percutaneous coronary intervention (PCI) and during recovery from non-ST-segment elevation myocardial infarction (NSTEMI). METHODS AND RESULTS: FMD was performed in accordance with a previously described technique in patients before and after PCI and in the recovery phase of NSTEMI, but in addition, L-FMC data were acquired from the last 30 s of cuff inflation. About 135 scans were performed in 96 participants (10 healthy volunteers and 86 patients). Measurement of brachial L-FMC was reproducible over hours. L-FMC was greater among patients with unstable vs. stable coronary atherosclerosis (-1.33 ±1.09% vs. -0.03 ± 1.26%, P < 0.01). Following PCI, FMD reduced (4.43 ± 2.93% vs. 1.66 ± 2.16%, P < 0.01) and L-FMC increased (-0.33 ± 0.76% vs. -1.63 ± 1.15%, P = 0.02). Furthermore, during convalescence from NSTEMI, L-FMC reduced (-1.37 ± 1.19% vs. 0.01 ± 0.82%, P = 0.02) in parallel with improvements in FMD (2.54 ± 2.19% vs. 5.15 ± 3.07%, P < 0.01). CONCLUSION: Brachial L-FMC can be measured reliably. Differences were observed between patients with stable and unstable coronary disease. L-FMC was acutely increased following PCI associated with reduced FMD and, in the recovery from NSTEMI, L-FMC reduced associated with increased FMD. These novel findings characterize acute and subacute variations in brachial L-FMC. The pathophysiological and clinical implications of these observations require further study.
Assuntos
Angioplastia Coronária com Balão , Artéria Braquial/fisiologia , Infarto do Miocárdio/terapia , Síndrome Coronariana Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Análise de Variância , Biomarcadores/metabolismo , Artéria Braquial/diagnóstico por imagem , Citocinas/metabolismo , Endotelina-1/metabolismo , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/fisiopatologia , Ultrassonografia , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
PURPOSE OF REVIEW: Niacin has been used for more than 50 years in the management of atherosclerosis and is associated with improved patient outcomes. The routine use of niacin has been superseded in recent years with the advent of newer lipid-modulating interventions. Recently, however, there has been a renewed interest in its use due to the appreciation of its many beneficial effects on atherosclerosis and endothelial function, both 'lipid-targeted' and 'pleiotropic'. This review will consider the effects of niacin in the setting of clinical trials and will critically evaluate proposed mechanisms of action. RECENT FINDINGS: The identification of the GPR109A receptor has promoted a greater insight into niacin's mechanism of action, with demonstrated beneficial effects on endothelial function and inflammation, in addition to its lipid modulation role. SUMMARY: Whether niacin itself is used routinely in the future will depend on the outcomes of two large outcome trials (AIM-HIGH and HPS2-THRIVE). In the future, however, with even better understanding of niacin pharmacology, new drugs may be able to be engineered to capture aspects of niacin that capitalize on the benefits more specifically and also more selectively, to avoid troublesome side-effects.
Assuntos
Aterosclerose/tratamento farmacológico , Hipolipemiantes/farmacologia , Niacina/farmacologia , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/tratamento farmacológico , Metabolismo dos Lipídeos/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: Nicotinic acid is the most potent treatment clinically available for lowering LDL cholesterol and VLDL cholesterol and raising HDL cholesterol. The strong inverse relationship between coronary heart disease risk and HDL cholesterol at all levels of LDL cholesterol has, therefore, given renewed emphasis on the therapeutic potential of niacin. The purpose of this review is to evaluate advances in the elucidation of mechanisms by which nicotinic acid affects the lipoprotein profile and, more recently, emerging evidence of nonlipid-mediated anti-inflammatory effects. RECENT FINDINGS: Niacin treatment reduces cardiovascular events and the progression of atherosclerosis. Identification of G-protein-coupled receptor 109A as the receptor for nicotinic acid has provided insights into how treatment with this compound leads to a favourable alteration in HDL cholesterol. In addition, evidence of nonlipid-mediated anti-inflammatory effects of nicotinic acid such as direct enhancement of adiponectin secretion demonstrates a novel atheroprotective role. SUMMARY: Whether nicotinic acid use becomes routine in the treatment of atherosclerosis is likely to be determined by the results of two ongoing clinical outcome trials. In addition, further research is required to explore the 'pleiotropic' effects of nicotinic acid and will ultimately provide a platform for the development of newer molecules that are potentially beneficial but without the well known side-effects.
Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/prevenção & controle , Niacina/uso terapêutico , HDL-Colesterol/metabolismo , LDL-Colesterol/metabolismo , Ensaios Clínicos como Assunto , Doença da Artéria Coronariana/metabolismo , HumanosRESUMO
OBJECTIVE: To investigate the effects of leptin, full-length adiponectin (fAd) and globular adiponectin (gAd), alone and in combination, on LNCaP and PC3 prostate cancer cell proliferation, and on the expression of p53 and bcl-2 gene expression. MATERIALS AND METHODS: LNCaP and PC3 prostate cancer cells were cultured and treated with the following: 0-100 nM leptin; 0-100 nM fAd +/- 100 nM leptin; 0-100 nM gAd +/- 100 nM leptin. Proliferation assays and quantitative reverse transcriptase-polymerase chain reaction for p53 tumour-suppressor gene and bcl-2 oncogene expression were performed on treated samples. RESULTS: Co-incubation of PC3 cells with 100 nM leptin and 1 or 100 nM fAd significantly decreased cell proliferation to approximately half of basal (P < 0.001); there was no significant effect in LNCaP cells. Leptin-induced inhibition of p53 expression in LNCaP cells was rescued by fAd. Leptin and fAd dose-dependently potentiated p53 expression in PC3 cells (P < 0.001); leptin and gAd also increased p53 expression (P < 0.05 and P < 0.001). fAd and gAd had no effect on bcl-2 expression in the presence of leptin in LNCaP cells. In PC3 cells, bcl-2 expression was inhibited to negligible levels in the presence of leptin. CONCLUSIONS: Leptin and adiponectin interact, resulting in the inhibition of prostate cancer cell proliferation, particularly in PC3 cells, via modulation of p53 and bcl-2 expression. Our findings support the notion that high leptin and low adiponectin levels may be important in driving obesity-related prostate cancer progression.
Assuntos
Adiponectina/metabolismo , Leptina/metabolismo , Obesidade/complicações , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Humanos , Masculino , Obesidade/metabolismo , Neoplasias da Próstata/complicaçõesRESUMO
BACKGROUND AND AIMS: Imaging studies have relied on the 'overall' volumetric quantification of perivascular adipose tissue. We sought to assess the relationship of circumferential distribution between perivascular adipose tissue and adjacent wall thickness of carotid and aortic arteries using dedicated magnetic resonance imaging sequences. METHODS: Vessel wall and perivascular adipose tissue were acquired using magnetic resonance imaging (1.5 T). Co-registered images were segmented separately, and measurements of both perivascular adipose tissue and vessel wall were obtained along radii of the vessel spaced at angles of 5° each. RESULTS: In total, 29 patients were recruited. Perivascular adipose tissue thickness of the aorta was 3.34 ± 0.79 mm with specific pattern of 'double peaks' distribution, while carotid perivascular adipose tissue had no identifiable pattern with thickness of 0.8 ± 0.91 mm. Although statistically significant, the correlation between perivascular adipose tissue thickness and wall thickness in carotid arteries with normal (r = 0.040, p = 0.001) or with abnormal wall thickness (r = -0.039, p = 0.015) was merely nominal. Similarly, perivascular adipose tissue of the aorta had very weak correlation with normal aortic wall thickness (r = 0.010, p = 0.008) but not with the abnormal ones (r = -0.05, p = 0.29). CONCLUSION: Dissociation between the spatial distribution of perivascular adipose tissue and arterial wall thickening in the aorta and carotid arteries does not support that perivascular adipose tissue has a causal role in promoting atherosclerotic plaque via a paracrine route. Yet, perivascular adipose tissue functional properties were not examined in this study.
Assuntos
Tecido Adiposo/diagnóstico por imagem , Aorta Torácica/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Placa Aterosclerótica , Tecido Adiposo/patologia , Idoso , Aorta Torácica/patologia , Doenças da Aorta/patologia , Aterosclerose/patologia , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/patologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos TestesRESUMO
Early detection of vascular inflammation would allow deployment of targeted strategies for the prevention or treatment of multiple disease states. Because vascular inflammation is not detectable with commonly used imaging modalities, we hypothesized that phenotypic changes in perivascular adipose tissue (PVAT) induced by vascular inflammation could be quantified using a new computerized tomography (CT) angiography methodology. We show that inflamed human vessels release cytokines that prevent lipid accumulation in PVAT-derived preadipocytes in vitro, ex vivo, and in vivo. We developed a three-dimensional PVAT analysis method and studied CT images of human adipose tissue explants from 453 patients undergoing cardiac surgery, relating the ex vivo images with in vivo CT scan information on the biology of the explants. We developed an imaging metric, the CT fat attenuation index (FAI), that describes adipocyte lipid content and size. The FAI has excellent sensitivity and specificity for detecting tissue inflammation as assessed by tissue uptake of 18F-fluorodeoxyglucose in positron emission tomography. In a validation cohort of 273 subjects, the FAI gradient around human coronary arteries identified early subclinical coronary artery disease in vivo, as well as detected dynamic changes of PVAT in response to variations of vascular inflammation, and inflamed, vulnerable atherosclerotic plaques during acute coronary syndromes. Our study revealed that human vessels exert paracrine effects on the surrounding PVAT, affecting local intracellular lipid accumulation in preadipocytes, which can be monitored using a CT imaging approach. This methodology can be implemented in clinical practice to noninvasively detect plaque instability in the human coronary vasculature.
Assuntos
Tecido Adiposo/irrigação sanguínea , Tecido Adiposo/patologia , Vasos Coronários/patologia , Imageamento Tridimensional , Inflamação/patologia , Adipócitos/patologia , Adipogenia , Diferenciação Celular , Proliferação de Células , Tamanho Celular , Vasos Coronários/diagnóstico por imagem , Citocinas/metabolismo , Humanos , Inflamação/diagnóstico por imagem , Lipídeos/química , Fenótipo , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Tomografia Computadorizada por Raios XRESUMO
Transcriptionally activated monocytes are recruited to the heart after acute myocardial infarction (AMI). After AMI in mice and humans, the number of extracellular vesicles (EVs) increased acutely. In humans, EV number correlated closely with the extent of myocardial injury. We hypothesized that EVs mediate splenic monocyte mobilization and program transcription following AMI. Some plasma EVs bear endothelial cell (EC) integrins, and both proinflammatory stimulation of ECs and AMI significantly increased VCAM-1-positive EV release. Injected EC-EVs localized to the spleen and interacted with, and mobilized, splenic monocytes in otherwise naive, healthy animals. Analysis of human plasma EV-associated miRNA showed 12 markedly enriched miRNAs after AMI; functional enrichment analyses identified 1,869 putative mRNA targets, which regulate relevant cellular functions (e.g., proliferation and cell movement). Furthermore, gene ontology termed positive chemotaxis as the most enriched pathway for the miRNA-mRNA targets. Among the identified EV miRNAs, EC-associated miRNA-126-3p and -5p were highly regulated after AMI. miRNA-126-3p and -5p regulate cell adhesion- and chemotaxis-associated genes, including the negative regulator of cell motility, plexin-B2. EC-EV exposure significantly downregulated plexin-B2 mRNA in monocytes and upregulated motility integrin ITGB2. These findings identify EVs as a possible novel signaling pathway by linking ischemic myocardium with monocyte mobilization and transcriptional activation following AMI.
Assuntos
Vesículas Extracelulares/metabolismo , Monócitos/metabolismo , Infarto do Miocárdio/patologia , Baço/patologia , Animais , Antígenos CD18/genética , Adesão Celular/genética , Quimiotaxia de Leucócito/genética , Regulação para Baixo , Células Endoteliais/metabolismo , Feminino , Expressão Gênica , Ontologia Genética , Células Endoteliais da Veia Umbilical Humana , Humanos , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Infarto do Miocárdio/metabolismo , Proteínas do Tecido Nervoso/genética , Células RAW 264.7 , RNA Mensageiro/metabolismo , Regulação para CimaRESUMO
CONTEXT: Polycystic ovary syndrome (PCOS) is a multifaceted metabolic disease linked with insulin resistance (IR) and obesity. Recent studies have shown that plasma levels of the insulin-mimetic adipokine visfatin increase with obesity. Currently, no data exist on the relative expression of visfatin in either plasma or adipose tissue of PCOS women. OBJECTIVES: We investigated the mRNA expression of visfatin from sc and omental (om) adipose tissue and sc adipocytes in women with PCOS compared with matched normal women, as well as visfatin protein in adipose tissue; plasma visfatin was also assessed. DESIGN: Real-time RT-PCR and Western blotting were used to assess the relative mRNA and protein expression of visfatin. Biochemical measurements were performed. RESULTS: There was significant up-regulation of visfatin mRNA in both sc (P < 0.05) and om (P < 0.05) adipose tissue of PCOS women, when compared with normal controls; these findings were also reflected in isolated sc adipocytes (PCOS > controls; P < 0.05). In addition to elevated plasma visfatin levels in women with PCOS (mean +/- sd, 30.2 +/- 10.4 vs. 11.2 +/- 6.2 ng/ml; P < 0.01) when compared with normal controls, visfatin protein levels were significantly greater in both sc and om adipose tissue of PCOS women (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: The precise reason for the up-regulation of visfatin seen in women with PCOS, a proinflammatory state, is unknown. Additional studies are needed to clarify the potential role of visfatin in the pathophysiology of PCOS.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Citocinas/metabolismo , Síndrome do Ovário Policístico/metabolismo , Adulto , Estudos de Casos e Controles , Células Cultivadas , Citocinas/sangue , Citocinas/genética , Feminino , Humanos , Gordura Intra-Abdominal/metabolismo , Antígenos Comuns de Leucócito/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Nicotinamida Fosforribosiltransferase , RNA Mensageiro/metabolismo , Gordura Subcutânea/metabolismoRESUMO
Preterm-born individuals have elevated blood pressure. We tested the hypothesis that this associates with an enhanced antiangiogenic circulating profile and that this association is mediated by variations in capillary density. We studied 204 adults aged 25 years (range, 20-30 years), of which 102 had been followed up prospectively since very preterm birth (mean gestational age, 30.3±2.5 weeks) and 102 were born term to uncomplicated pregnancies. A panel of circulating biomarkers, including soluble endoglin and soluble fms-like tyrosine kinase-1, were compared between groups and related to perinatal history and adult cardiovascular risk. Associations with cardiovascular phenotype were studied in 90 individuals who had undergone detailed assessment of microvascular, macrovascular, and cardiac structure and function. Preterm-born individuals had elevations in soluble endoglin (5.64±1.03 versus 4.06±0.85 ng/mL; P<0.001) and soluble fms-like tyrosine kinase-1 (88.1±19.0 versus 73.0±15.3 pg/mL; P<0.001) compared with term-born individuals, proportional to elevations in resting and ambulatory blood pressure, as well as degree of prematurity (P<0.05). Maternal hypertensive pregnancy disorder was associated with additional increases in soluble fms-like tyrosine kinase-1 (P=0.002). Other circulating biomarkers, including those of inflammation and endothelial activation, were not related to blood pressure. There was a specific graded association between soluble endoglin and degree of functional and structural capillary rarefaction (P=0.002 and P<0.001), and in multivariable analysis, there were capillary density-mediated associations between soluble endoglin and blood pressure. Preterm-born individuals exhibit an enhanced antiangiogenic state in adult life that is specifically related to elevations in blood pressure. The association seems to be mediated through capillary rarefaction and is independent of other cardiovascular structural and functional differences in the offspring.
Assuntos
Filhos Adultos , Hipertensão/fisiopatologia , Microvasos/fisiopatologia , Neovascularização Patológica/fisiopatologia , Nascimento Prematuro/fisiopatologia , Adulto , Antígenos CD/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Endoglina , Feminino , Seguimentos , Humanos , Hipertensão/epidemiologia , Masculino , Prevalência , Estudos Prospectivos , Receptores de Superfície Celular/sangue , Fatores de Risco , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangueRESUMO
Oxidative stress plays a critical role in the vascular complications of type 2 diabetes. We examined the effect of type 2 diabetes on NADPH oxidase in human vessels and explored the mechanisms of this interaction. Segments of internal mammary arteries (IMAs) with their perivascular adipose tissue (PVAT) and thoracic adipose tissue were obtained from 386 patients undergoing coronary bypass surgery (127 with type 2 diabetes). Type 2 diabetes was strongly correlated with hypoadiponectinemia and increased vascular NADPH oxidase-derived superoxide anions (O2Ë(-)). The genetic variability of the ADIPOQ gene and circulating adiponectin (but not interleukin-6) were independent predictors of NADPH oxidase-derived O2Ë(-). However, adiponectin expression in PVAT was positively correlated with vascular NADPH oxidase-derived O2Ë(-). Recombinant adiponectin directly inhibited NADPH oxidase in human arteries ex vivo by preventing the activation/membrane translocation of Rac1 and downregulating p22(phox) through a phosphoinositide 3-kinase/Akt-mediated mechanism. In ex vivo coincubation models of IMA/PVAT, the activation of arterial NADPH oxidase triggered a peroxisome proliferator-activated receptor-γ-mediated upregulation of the adiponectin gene in the neighboring PVAT via the release of vascular oxidation products. We demonstrate for the first time in humans that reduced adiponectin levels in individuals with type 2 diabetes stimulates vascular NADPH oxidase, while PVAT "senses" the increased NADPH oxidase activity in the underlying vessel and responds by upregulating adiponectin gene expression. This PVAT-vessel interaction is identified as a novel therapeutic target for the prevention of vascular complications of type 2 diabetes.
Assuntos
Adiponectina/metabolismo , Tecido Adiposo/metabolismo , Artérias/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , NADPH Oxidases/metabolismo , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Elevated islet uncoupling protein-2 (UCP-2) impairs beta-cell function and UCP-2 may be increased in clinical obesity and diabetes. We investigated the effects of glucose and leptin on UCP-2 expression in isolated human islets. Human islets were incubated for 24 h with glucose (5.5-22 mmol/l)+/-leptin (0-10 nmol/l). Some islet batches were incubated at high (22 mmol/l), and subsequently lower (5.5 mmol/l), glucose to assess reversibility of effects. Leptin effects on insulin release were also measured. Glucose dose-dependently increased UCP-2 expression in all islet batches, maximally by three-fold. This was not fully reversed by subsequently reduced glucose levels. Leptin decreased UCP-2 expression by up to 75%, and maximally inhibited insulin release by 47%, at 22 mmol/l glucose. This is the first report of UCP-2 expression in human islets and provides novel evidence of its role in the loss of beta-cell function in diabetes.