Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 18 de 18
Filtrar
1.
JACC Basic Transl Sci ; 5(4): 360-373, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32368695

RESUMO

This study showed that treatment with a therapeutic monoclonal immunoglobulin-G1 antibody against phosphorylcholine on oxidized phospholipids preserves coronary flow reserve and attenuates atherosclerotic inflammation as determined by the uptake of 18F-fluorodeoxyglucose in atherosclerotic mice. The noninvasive imaging techniques represent translational tools to assess the efficacy of phosphorylcholine-targeted therapy on coronary artery function and atherosclerosis in clinical studies.

2.
Atherosclerosis ; 305: 64-72, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386751

RESUMO

BACKGROUND AND AIMS: Dipeptidyl peptidase 4 (DPP-4) inhibitors have anti-inflammatory and atheroprotective effects. We evaluated the effects of the DPP-4 inhibitor linagliptin on atherosclerotic plaque and hepatic inflammation using histology and 2-deoxy-2-[18F]-fluoro-d-glucose (18F-FDG), a positron emission tomography tracer of inflammation, in a mouse model of hypercholesterolemia and type 2 diabetes. METHODS: Igf2/Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 8 weeks and then randomly allocated to receive HFD (n = 14), or HFD with added linagliptin (n = 15) for additional 12 weeks. Five mice fed a chow diet were studied as an additional control. At the end of the study, glucose tolerance, aortic and liver uptake of 18F-FDG, and histology were studied. RESULTS: Mice in linagliptin and HFD groups had similar fasting glucose concentrations, but linagliptin improved glucose tolerance. Aortas of linagliptin and HFD groups showed advanced atherosclerotic plaques with no difference in the mean intima-to-media ratio or number of macrophages in the plaques. Autoradiography showed similar 18F-FDG uptake by atherosclerotic plaques in linagliptin and HFD groups (plaque-to-wall ratio: 1.7 ± 0.25 vs. 1.6 ± 0.21; p = 0.24). In the liver, linagliptin reduced the histologic inflammation score but had no effect on 18F-FDG uptake. Compared with chow diet, uptake of 18F-FDG was similar in the aorta, but higher in the liver after HFD. CONCLUSIONS: Linagliptin therapy improved glucose tolerance and reduced hepatic inflammation but had no effect on plaque burden or atherosclerotic inflammation, as determined by histology and 18F-FDG uptake, in atherosclerotic mice with type 2 diabetes.


Assuntos
Aterosclerose , Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/uso terapêutico , Placa Aterosclerótica , Animais , Aterosclerose/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dipeptidil Peptidase 4 , Fluordesoxiglucose F18 , Inflamação/tratamento farmacológico , Camundongos , Camundongos Knockout , Tomografia por Emissão de Pósitrons
3.
Molecules ; 24(6)2019 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-30893771

RESUMO

Atherosclerosis is characterized by the accumulation of oxidized lipids in the artery wall, which triggers an inflammatory response. Oxidized low-density lipoprotein (ox-LDL) presents amyloid-like structural properties, and different amyloid species have recently been recognized in atherosclerotic plaques. Therefore, we studied the uptake of the amyloid imaging agent [18F]Flutemetamol in atherosclerotic plaques. The binding of [18F]Flutemetamol to human carotid artery plaque was studied in vitro. In vivo uptake of the tracer was studied in hypercholesterolemic IGF-II/LDLR-/-ApoB100/100 mice and C57BL/6N controls. Tracer biodistribution was studied in vivo with PET/CT, and ex vivo by gamma counter and digital ex vivo autoradiography. The presence of amyloid, ox-LDL, and macrophages in the plaques was examined by immunohistochemistry. [18F]Flutemetamol showed specific accumulation in human carotid plaque, especially in areas positive for amyloid beta. The aortas of IGF-II/LDLR-/-ApoB100/100 mice showed large thioflavin-S-positive atherosclerotic plaques containing ox-LDL and macrophages. Autoradiography revealed 1.7-fold higher uptake in the plaques than in a lesion-free vessel wall, but no difference in aortic tissue uptake between mouse strains were observed in the in vivo PET/CT. In conclusion, [18F]Flutemetamol binds to amyloid-positive areas in human atherosclerotic plaques. Further studies are warranted to clarify the uptake mechanisms, and the potential of the tracer for in vivo imaging of atherosclerosis in patients.


Assuntos
Aterosclerose/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Autorradiografia , Feminino , Humanos , Imuno-Histoquímica , Lipoproteínas LDL/metabolismo , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL
4.
Sci Rep ; 8(1): 9720, 2018 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-29946129

RESUMO

Inflammation plays an important role in the development of atherosclerosis and its complications. Because the folate receptor ß (FR-ß) is selectively expressed on macrophages, an FR targeted imaging agent could be useful for assessment of atherosclerotic inflammation. We investigated aluminum fluoride-18-labeled 1,4,7-triazacyclononane-1,4,7-triacetic acid conjugated folate (18F-FOL) for the detection of atherosclerotic plaque inflammation. We studied atherosclerotic plaques in mice, rabbits, and human tissue samples using 18F-FOL positron emission tomography/computed tomography (PET/CT). Compound 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) was used as a comparison. Firstly, we found that the in vitro binding of 18F-FOL co-localized with FR-ß-positive macrophages in carotid endarterectomy samples from patients with recent ischemic symptoms. We then demonstrated specific accumulation of intravenously administered 18F-FOL in atherosclerotic plaques in mice and rabbits using PET/CT. We noticed that the 18F-FOL uptake correlated with the density of macrophages in plaques and provided a target-to-background ratio as high as 18F-FDG, but with considerably lower myocardial uptake. Thus, 18F-FOL PET/CT targeting of FR-ß-positive macrophages presents a promising new tool for the in vivo imaging of atherosclerotic inflammation.


Assuntos
Compostos de Alumínio/química , Fluoretos/química , Fluordesoxiglucose F18/química , Inflamação/diagnóstico por imagem , Placa Aterosclerótica/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Animais , Feminino , Humanos , Masculino , Camundongos , Coelhos
5.
Diabetes Res Clin Pract ; 131: 208-216, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28778047

RESUMO

AIMS: Metformin therapy is associated with diffuse intestinal 18F-fluoro-deoxyglucose (FDG) accumulation in clinical diagnostics using routine FDG-PET imaging. We aimed to study whether metformin induced glucose uptake in intestine is associated with the improved glycaemic control in patients with type 2 diabetes. Therefore, we compared the effects of metformin and rosiglitazone on intestinal glucose metabolism in patients with type 2 diabetes in a randomized placebo controlled clinical trial, and further, to understand the underlying mechanism, evaluated the effect of metformin in rats. METHODS: Forty-one patients with newly diagnosed type 2 diabetes were randomized to metformin (1g, b.i.d), rosiglitazone (4mg, b.i.d), or placebo in a 26-week double-blind trial. Tissue specific intestinal glucose uptake was measured before and after the treatment period using FDG-PET during euglycemic hyperinsulinemia. In addition, rats were treated with metformin or vehicle for 12weeks, and intestinal FDG uptake was measured in vivo and with autoradiography. RESULTS: Glucose uptake increased 2-fold in the small intestine and 3-fold in the colon for the metformin group and associated with improved glycemic control. Rosiglitazone increased only slightly intestinal glucose uptake. In rodents, metformin treatment enhanced intestinal FDG retention (P=0.002), which was localized in the mucosal enterocytes of the small intestine. CONCLUSIONS: Metformin treatment significantly enhances intestinal glucose uptake from the circulation of patients with type 2 diabetes. This intestine-specific effect is associated with improved glycemic control and localized to mucosal layer. These human findings demonstrate directs effect of metformin on intestinal metabolism and elucidate the actions of metformin. Clinical trial number NCT02526615.


Assuntos
Glicemia/metabolismo , Hipoglicemiantes/uso terapêutico , Mucosa Intestinal/metabolismo , Metformina/uso terapêutico , Tiazolidinedionas/uso terapêutico , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Método Duplo-Cego , Humanos , Masculino , Metformina/farmacologia , Pessoa de Meia-Idade , Ratos , Rosiglitazona , Tiazolidinedionas/farmacologia
6.
Atherosclerosis ; 263: 369-376, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28457625

RESUMO

BACKGROUND AND AIMS: Uptake of the positron emission tomography (PET) tracer 2-deoxy-2-[18F]-fluoro-d- glucose ([18F]FDG) into macrophages is a sensitive marker of inflammation in atherosclerosis. To assess the anti-inflammatory effects of statins, we studied whether atorvastatin therapy reduces aortic [18F]FDG uptake in hypercholesterolemic mice deficient in low-density lipoprotein receptor (Ldlr), and expressing only apolipoprotein B-100 (Ldlr-/-Apob100/100). METHODS: Thirty-six Ldlr-/-Apob100/100 mice were fed a high-fat diet (HFD) for 12 weeks and then allocated to receive a HFD (n = 13), chow diet (Chow, n = 12), or HFD with added atorvastatin (HFD + A, n = 11), for another 12 weeks. In addition to aortic histopathology, [18F]FDG uptake was studied in vivo using PET/computed tomography (CT), and ex vivo by gamma counting of excised aorta. RESULTS: Total cholesterol levels were lower in the Chow and HFD + A groups than in the HFD group (10 ± 3.2, 23 ± 4.9 and 34 ± 9.2 mmol/l, respectively), with the Chow group also showing a lower plaque burden and lower numbers of macrophages in the lesions. Compared to the HFD group, [18F]FDG uptake in the aorta (normalized for blood) was lower in the Chow group in both in vivo (2.1 ± 0.21 vs. 1.7 ± 0.25, p = 0.018) and ex vivo (5.2 ± 2.3 vs. 2.8 ± 0.87, p = 0.011) analyses, whereas atorvastatin had no effect on uptake (2.1 ± 0.42 in vivo and 3.9 ± 1.8 ex vivo). [18F]FDG uptake correlated with plasma total cholesterol levels. CONCLUSIONS: Atorvastatin therapy did not show cholesterol-independent effects on inflammation in atherosclerotic lesions in Ldlr-/-Apob100/100 mice, as determined by histology and [18F]FDG PET, whereas a cholesterol-lowering diet intervention was effective.


Assuntos
Doenças da Aorta/prevenção & controle , Apolipoproteína B-100/deficiência , Aterosclerose/prevenção & controle , Atorvastatina/farmacologia , Dieta com Restrição de Gorduras , Fluordesoxiglucose F18/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/prevenção & controle , Placa Aterosclerótica , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos/administração & dosagem , Receptores de LDL/deficiência , Ração Animal , Animais , Doenças da Aorta/sangue , Doenças da Aorta/diagnóstico por imagem , Doenças da Aorta/genética , Apolipoproteína B-100/genética , Aterosclerose/sangue , Aterosclerose/diagnóstico por imagem , Aterosclerose/genética , Dieta Hiperlipídica , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Inflamação/sangue , Inflamação/diagnóstico por imagem , Inflamação/genética , Lipídeos/sangue , Masculino , Camundongos Knockout , Fenótipo , Receptores de LDL/genética , Fatores de Tempo
7.
Eur Heart J ; 38(5): 349-361, 2017 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-28201733

RESUMO

Aims: The benefit of the ß1-adrenergic receptor (ß1-AR) agonist dobutamine for treatment of acute heart failure in peripartum cardiomyopathy (PPCM) is controversial. Cardiac STAT3 expression is reduced in PPCM patients. Mice carrying a cardiomyocyte-restricted deletion of STAT3 (CKO) develop PPCM. We hypothesized that STAT3-dependent signalling networks may influence the response to ß-AR agonist treatment in PPCM patients and analysed this hypothesis in CKO mice. Methods and Results: Follow-up analyses in 27 patients with severe PPCM (left ventricular ejection fraction ≤25%) revealed that 19 of 20 patients not obtaining dobutamine improved cardiac function. All seven patients obtaining dobutamine received heart transplantation (n = 4) or left ventricular assist devices (n = 3). They displayed diminished myocardial triglyceride, pyruvate, and lactate content compared with non-failing controls. The ß-AR agonist isoproterenol (Iso) induced heart failure with high mortality in postpartum female, in non-pregnant female and in male CKO, but not in wild-type mice. Iso induced heart failure and high mortality in CKO mice by impairing fatty acid and glucose uptake, thereby generating a metabolic deficit. The latter was governed by disturbed STAT3-dependent signalling networks, microRNA-199a-5p, microRNA-7a-5p, insulin/glucose transporter-4, and neuregulin/ErbB signalling. The resulting cardiac energy depletion and oxidative stress promoted dysfunction and cardiomyocyte loss inducing irreversible heart failure, which could be attenuated by the ß1-AR blocker metoprolol or glucose-uptake-promoting drugs perhexiline and etomoxir. Conclusions: Iso impairs glucose uptake, induces energy depletion, oxidative stress, dysfunction, and death in STAT3-deficient cardiomyocytes mainly via ß1-AR stimulation. These cellular alterations may underlie the dobutamine-induced irreversible heart failure progression in PPCM patients who frequently display reduced cardiac STAT3 expression.


Assuntos
Agonistas de Receptores Adrenérgicos beta 1/efeitos adversos , Agonistas de Receptores Adrenérgicos beta 1/toxicidade , Cardiomiopatias/induzido quimicamente , Dobutamina/efeitos adversos , Insuficiência Cardíaca/tratamento farmacológico , Transtornos Puerperais/tratamento farmacológico , Fator de Transcrição STAT3/fisiologia , Adulto , Animais , Glicemia/metabolismo , Feminino , Humanos , Isoproterenol/farmacologia , Masculino , Camundongos Knockout , MicroRNAs/fisiologia , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Período Periparto , Nucleotídeos de Purina/metabolismo , Distribuição Aleatória , Espécies Reativas de Oxigênio/metabolismo , Receptor ErbB-4/metabolismo , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/deficiência , Disfunção Ventricular Esquerda/induzido quimicamente
8.
PLoS One ; 12(1): e0169964, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28129334

RESUMO

Sunitinib is a tyrosine kinase inhibitor approved for the treatment of multiple solid tumors. However, cardiotoxicity is of increasing concern, with a need to develop rational mechanism driven approaches for the early detection of cardiac dysfunction. We sought to interrogate changes in cardiac energy substrate usage during sunitinib treatment, hypothesising that these changes could represent a strategy for the early detection of cardiotoxicity. Balb/CJ mice or Sprague-Dawley rats were treated orally for 4 weeks with 40 or 20 mg/kg/day sunitinib. Cardiac positron emission tomography (PET) was implemented to investigate alterations in myocardial glucose and oxidative metabolism. Following treatment, blood pressure increased, and left ventricular ejection fraction decreased. Cardiac [18F]-fluorodeoxyglucose (FDG)-PET revealed increased glucose uptake after 48 hours. [11C]Acetate-PET showed decreased myocardial perfusion following treatment. Electron microscopy revealed significant lipid accumulation in the myocardium. Proteomic analyses indicated that oxidative metabolism, fatty acid ß-oxidation and mitochondrial dysfunction were among the top myocardial signalling pathways perturbed. Sunitinib treatment results in an increased reliance on glycolysis, increased myocardial lipid deposition and perturbed mitochondrial function, indicative of a fundamental energy crisis resulting in compromised myocardial energy metabolism and function. Our findings suggest that a cardiac PET strategy may represent a rational approach to non-invasively monitor metabolic pathway remodeling following sunitinib treatment.


Assuntos
Coração/diagnóstico por imagem , Indóis/efeitos adversos , Redes e Vias Metabólicas/efeitos dos fármacos , Tomografia por Emissão de Pósitrons , Pirróis/efeitos adversos , Animais , Fluordesoxiglucose F18/uso terapêutico , Coração/efeitos dos fármacos , Humanos , Indóis/administração & dosagem , Masculino , Miocárdio/metabolismo , Miocárdio/patologia , Proteômica , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Sunitinibe , Função Ventricular Esquerda/efeitos dos fármacos
9.
J Nucl Cardiol ; 24(3): 862-871, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-27225517

RESUMO

BACKGROUND: Radioligands of 18-kDa translocator protein (TSPO) expressed on activated macrophages are a potential approach for imaging of inflammation in atherosclerosis. We evaluated a novel TSPO-targeted tracer 18F-FEMPA for the detection of atherosclerotic plaque inflammation in mice. METHODS AND RESULTS: The distribution kinetics of 18F-FEMPA was evaluated by in vivo PET/CT imaging. 18F-FEMPA uptake was compared in atherosclerotic (LDLR-/-ApoB100/100, n = 10) and healthy mice (C57BL/6 N, n = 7) ex vivo at twenty minutes post-injection. Biodistribution was analyzed from harvested tissue samples, and aortas were sectioned for autoradiography. Aortas of LDLR-/-ApoB100/100 mice showed large, macrophage-rich atherosclerotic plaques. In vivo, 18F-FEMPA showed rapid blood clearance but no difference in aortic uptake between atherosclerotic and healthy mice. In the mice studied ex vivo at 20 minutes post-injection, quantification of radioactivity in the whole aorta showed 1.3-fold higher 18F-FEMPA accumulation in atherosclerotic than healthy mice (P = .028). Autoradiography showed higher tracer uptake in plaque areas with high macrophage content as compared with areas of no macrophages (count densities 190 ± 54 vs 40 ± 13 PSL/mm2, P < .001), but the uptake in the plaques was not higher than in the normal vessel wall (230 ± 78 PSL/mm2). In vitro blocking showed specific accumulation in mouse and human atherosclerotic plaques. Immunohistochemistry confirmed co-localization of TSPO and macrophages. CONCLUSIONS: 18F-FEMPA shows rapid blood clearance and uptake in the mouse aorta. Uptake in atherosclerotic plaques correlated with the amount of macrophages, but did not exceed that in the normal vessel wall.


Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Hidrocarbonetos Fluorados/farmacocinética , Piridinas/farmacocinética , Receptores de GABA/metabolismo , Animais , Biomarcadores/metabolismo , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Especificidade de Órgãos , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição Tecidual
10.
Contrast Media Mol Imaging ; 2017: 7645070, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29463960

RESUMO

Sialic acid-binding immunoglobulin-like lectin 9 (Siglec-9) is a ligand of inflammation-inducible vascular adhesion protein-1 (VAP-1). We compared 68Ga-DOTA- and 18F-fluorodeoxyribose- (FDR-) labeled Siglec-9 motif peptides for PET imaging of inflammation. Methods. Firstly, we examined 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 in rats with skin/muscle inflammation. We then studied 18F-FDR-Siglec-9 for the detection of inflamed atherosclerotic plaques in mice and compared it with previous 68Ga-DOTA-Siglec-9 results. Lastly, we estimated human radiation dosimetry from the rat data. Results. In rats, 68Ga-DOTA-Siglec-9 (SUV, 0.88 ± 0.087) and 18F-FDR-Siglec-9 (SUV, 0.77 ± 0.22) showed comparable (P = 0.29) imaging of inflammation. In atherosclerotic mice, 18F-FDR-Siglec-9 detected inflamed plaques with a target-to-background ratio (1.6 ± 0.078) similar to previously tested 68Ga-DOTA-Siglec-9 (P = 0.35). Human effective dose estimates for 68Ga-DOTA-Siglec-9 and 18F-FDR-Siglec-9 were 0.024 and 0.022 mSv/MBq, respectively. Conclusion. Both tracers are suitable for PET imaging of inflammation. The easier production and lower cost of 68Ga-DOTA-Siglec-9 present advantages over 18F-FDR-Siglec-9, indicating it as a primary choice for clinical studies.


Assuntos
Dermatite/diagnóstico por imagem , Fluordesoxiglucose F18/farmacologia , Radioisótopos de Gálio/farmacologia , Miosite/diagnóstico por imagem , Compostos Organometálicos/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/farmacologia , Animais , Inflamação/diagnóstico por imagem , Miosite/diagnóstico , Radiometria , Ratos , Ratos Sprague-Dawley
11.
Sci Rep ; 6: 35089, 2016 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-27731409

RESUMO

Given the important role of inflammation and the potential association of the leukocyte trafficking-associated adhesion molecule vascular adhesion protein 1 (VAP-1) with atherosclerosis, this study examined whether functional VAP-1 is expressed in atherosclerotic lesions and, if so, whether it could be targeted by positron emission tomography (PET). First, immunohistochemistry revealed that VAP-1 localized to endothelial cells of intra-plaque neovessels in human carotid endarterectomy samples from patients with recent ischemic symptoms. In low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 (LDLR-/-ApoB100/100), VAP-1 was expressed on endothelial cells lining inflamed atherosclerotic lesions; normal vessel walls in aortas of C57BL/6N control mice were VAP-1-negative. Second, we discovered that the focal uptake of VAP-1 targeting sialic acid-binding immunoglobulin-like lectin 9 based PET tracer [68Ga]DOTA-Siglec-9 in atherosclerotic plaques was associated with the density of activated macrophages (r = 0.58, P = 0.022). As a final point, we found that the inhibition of VAP-1 activity with small molecule LJP1586 decreased the density of macrophages in inflamed atherosclerotic plaques in mice. Our results suggest for the first time VAP-1 as a potential imaging target for inflamed atherosclerotic plaques, and corroborate VAP-1 inhibition as a therapeutic approach in the treatment of atherosclerosis.


Assuntos
Amina Oxidase (contendo Cobre)/metabolismo , Moléculas de Adesão Celular/metabolismo , Placa Aterosclerótica/metabolismo , Adulto , Animais , Antígenos CD/metabolismo , Apolipoproteína B-100/metabolismo , Estenose das Carótidas/diagnóstico por imagem , Estenose das Carótidas/metabolismo , Estenose das Carótidas/patologia , Feminino , Radioisótopos de Gálio , Compostos Heterocíclicos com 1 Anel , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ensaio Radioligante , Receptores de LDL/deficiência , Receptores de LDL/genética , Lectinas Semelhantes a Imunoglobulina de Ligação ao Ácido Siálico/metabolismo
12.
Cardiovasc Diabetol ; 15: 26, 2016 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-26852231

RESUMO

BACKGROUND: Diabetes is a risk factor for atherosclerosis associated with oxidative stress, inflammation and cell proliferation. The purpose of this study was to evaluate arterial choline uptake and its relationship to atherosclerotic inflammation in diabetic and non-diabetic hypercholesterolemic mice. METHODS: Low-density lipoprotein-receptor deficient mice expressing only apolipoprotein B100, with or without type 2 diabetes caused by pancreatic overexpression of insulin-like growth factor II (IGF-II/LDLR(-/-)ApoB(100/100) and LDLR(-/-)ApoB(100/100)) were studied. Distribution kinetics of choline analogue (18)F-fluoromethylcholine ((18)F-FMCH) was assessed in vivo by positron emission tomography (PET) imaging. Then, aortic uptakes of (18)F-FMCH and glucose analogue (18)F-fluorodeoxyglucose ((18)F-FDG), were assessed ex vivo by gamma counting and autoradiography of tissue sections. The (18)F-FMCH uptake in atherosclerotic plaques was further compared with macrophage infiltration and the plasma levels of cytokines and metabolic markers. RESULTS: The aortas of all hypercholesterolemic mice showed large, macrophage-rich atherosclerotic plaques. The plaque burden and densities of macrophage subtypes were similar in diabetic and non-diabetic animals. The blood clearance of (18)F-FMCH was rapid. Both the absolute (18)F-FMCH uptake in the aorta and the aorta-to-blood uptake ratio were higher in diabetic than in non-diabetic mice. In autoradiography, the highest (18)F-FMCH uptake co-localized with macrophage-rich atherosclerotic plaques. (18)F-FMCH uptake in plaques correlated with levels of total cholesterol, insulin, C-peptide and leptin. In comparison with (18)F-FDG, (18)F-FMCH provided similar or higher plaque-to-background ratios in diabetic mice. CONCLUSIONS: Type 2 diabetes enhances the uptake of choline that reflects inflammation in atherosclerotic plaques in mice. PET tracer (18)F-FMCH is a potential tool to study vascular inflammation associated with diabetes.


Assuntos
Aorta/diagnóstico por imagem , Doenças da Aorta/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Colina/análogos & derivados , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/diagnóstico por imagem , Radioisótopos de Flúor , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Animais , Aorta/metabolismo , Doenças da Aorta/sangue , Doenças da Aorta/etiologia , Doenças da Aorta/metabolismo , Aterosclerose/sangue , Aterosclerose/etiologia , Aterosclerose/metabolismo , Biomarcadores/sangue , Colina/administração & dosagem , Colina/farmacocinética , Citocinas/sangue , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Modelos Animais de Doenças , Hipercolesterolemia , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Placa Aterosclerótica , Valor Preditivo dos Testes , Compostos Radiofarmacêuticos/administração & dosagem , Distribuição Tecidual
13.
J Ultrasound Med ; 33(11): 1941-8, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25336481

RESUMO

OBJECTIVES: Coronary microvascular dysfunction, observed as impaired coronary vasodilator capacity, is an early manifestation of coronary artery disease. Inflammation plays an important role in different stages of atherogenesis. To study the role of vessel wall inflammation in the development of coronary dysfunction, we compared [(18)F]fluorodeoxyglucose (FDG) uptake in the aorta and coronary flow reserve (CFR) in atherosclerotic mice. METHODS: We studied healthy young C57BL/6 mice fed a normal diet (n = 7) as well as hypercholesterolemic low-density lipoprotein receptor-disrupted/apolipoprotein B100-expressing (LDLR(-/-)ApoB(100/100)) mice (n = 15) and hypercholesterolemic and diabetic LDLR(-/-)ApoB(100/100)insulinlike growth factor II-overexpressing mice (n = 14) fed a western-type diet, aged 4 to 6 months. Doppler sonography was used to measure CFR as the ratio of coronary flow velocity during isoflurane-induced hyperemia and at rest. Uptake of [(18)F]FDG into the aorta was measured by autoradiography of tissue sections. RESULTS: Histologic sections showed extensive atherosclerosis in the aorta, but coronary arteries were not obstructed. Both hyperemic coronary flow velocity and CFR were reduced (P < .05) in hypercholesterolemic mice with and without diabetes in comparison to healthy young C57BL/6 controls. Among hypercholesterolemic mice, both hyperemic flow velocity and CFR inversely correlated with atherosclerotic plaque [(18)F]FDG uptake in the aorta (r = -0.73; P < .001; r = -0.63; P = .001, respectively). In a multivariate analysis, including animal weight, aortic plaque burden, plasma glucose, plasma cholesterol, and [(18)F]FDG uptake in atherosclerotic plaques, only [(18)F]FDG uptake remained an independent predictor of reduced CFR (ß = 0.736; P = .001). CONCLUSIONS: The inflammatory activity in atherosclerotic plaques of the aorta independently predicts reduced CFR in atherosclerotic mice without obstructive coronary artery disease. This finding suggests that atherosclerotic inflammation contributes to coronary dysfunction.


Assuntos
Aortite/metabolismo , Doença da Artéria Coronariana/metabolismo , Fluordesoxiglucose F18/farmacocinética , Reserva Fracionada de Fluxo Miocárdico , Tomografia por Emissão de Pósitrons/métodos , Animais , Aortite/complicações , Aortite/diagnóstico por imagem , Simulação por Computador , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Feminino , Interpretação de Imagem Assistida por Computador/métodos , Masculino , Taxa de Depuração Metabólica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Cardiovasculares , Compostos Radiofarmacêuticos/farmacocinética , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
14.
Arterioscler Thromb Vasc Biol ; 34(7): 1346-54, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24790139

RESUMO

OBJECTIVE: Melanocortin peptides have been shown to elicit anti-inflammatory actions and to promote vascular endothelial function by activating type 1 and 3 melanocortin receptors. Here, we addressed whether these favorable properties of melanocortins could reduce atherosclerotic plaque inflammation and improve vasoreactivity in atherosclerotic mice. APPROACH AND RESULTS: Low-density lipoprotein receptor-deficient mice expressing only apolipoprotein B100 were fed a high-fat diet for 8 or 16 weeks and treated with either vehicle or a stable melanocortin analog, melanotan II (MT-II, 0.3 mg/kg per day, 4 weeks). We determined plaque uptake of fluorine-18-labeled fluorodeoxyglucose as a surrogate marker for atherosclerotic plaque inflammation and vascular function of the aorta by ex vivo analyses. MT-II had no effect on body weight or composition, or plasma cholesterol levels in atherosclerotic mice. Without attenuating atherosclerotic lesion size or lesional macrophage accumulation, MT-II treatment reduced fluorine-18-labeled fluorodeoxyglucose uptake in the atherosclerotic plaques. Resident macrophages in the lesions of MT-II-treated mice were polarized toward the anti-inflammatory M2 phenotype. Systemic inflammation was also attenuated by MT-II intervention as evidenced by decreased plasma levels of proinflammatory cytokines. In terms of aortic vasoreactivity, MT-II-treated mice showed enhanced endothelium-dependent relaxations, as well as promotion of vascular sensitivity to nitric oxide-mediated vasodilation, which were markedly impaired in control mice after prolonged duration of diet exposure. CONCLUSIONS: The present study demonstrates that pharmacological activation of the melanocortin system has therapeutic benefits in pre-established atherosclerosis by limiting plaque inflammation and promoting vascular endothelial function, which may provide a novel therapeutic approach for atherosclerosis.


Assuntos
Anti-Inflamatórios/farmacologia , Aorta/efeitos dos fármacos , Aterosclerose/prevenção & controle , Endotélio Vascular/efeitos dos fármacos , Inflamação/prevenção & controle , Peptídeos Cíclicos/farmacologia , Placa Aterosclerótica , Receptores de Melanocortina/agonistas , Vasodilatação/efeitos dos fármacos , alfa-MSH/análogos & derivados , Animais , Aorta/diagnóstico por imagem , Aorta/imunologia , Aorta/metabolismo , Aorta/patologia , Aorta/fisiopatologia , Apolipoproteínas B/genética , Apolipoproteínas B/metabolismo , Aterosclerose/sangue , Aterosclerose/diagnóstico , Aterosclerose/imunologia , Aterosclerose/fisiopatologia , Biomarcadores/sangue , Dieta Hiperlipídica , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Endotélio Vascular/imunologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/imunologia , Inflamação/fisiopatologia , Mediadores da Inflamação/sangue , Lipídeos/sangue , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Fenótipo , Cintilografia , Receptores de LDL/deficiência , Receptores de LDL/genética , Receptores de Melanocortina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatadores/farmacologia , alfa-MSH/farmacologia
15.
EMBO Mol Med ; 6(3): 307-21, 2014 03.
Artigo em Inglês | MEDLINE | ID: mdl-24448490

RESUMO

Angiogenic growth factors have recently been linked to tissue metabolism. We have used genetic gain- and loss-of function models to elucidate the effects and mechanisms of action of vascular endothelial growth factor-B (VEGF-B) in the heart. A cardiomyocyte-specific VEGF-B transgene induced an expanded coronary arterial tree and reprogramming of cardiomyocyte metabolism. This was associated with protection against myocardial infarction and preservation of mitochondrial complex I function upon ischemia-reperfusion. VEGF-B increased VEGF signals via VEGF receptor-2 to activate Erk1/2, which resulted in vascular growth. Akt and mTORC1 pathways were upregulated and AMPK downregulated, readjusting cardiomyocyte metabolic pathways to favor glucose oxidation and macromolecular biosynthesis. However, contrasting with a previous theory, there was no difference in fatty acid uptake by the heart between the VEGF-B transgenic, gene-targeted or wildtype rats. Importantly, we also show that VEGF-B expression is reduced in human heart disease. Our data indicate that VEGF-B could be used to increase the coronary vasculature and to reprogram myocardial metabolism to improve cardiac function in ischemic heart disease.


Assuntos
Isquemia Miocárdica/prevenção & controle , Miocárdio/metabolismo , Fator B de Crescimento do Endotélio Vascular/metabolismo , Adenoviridae/genética , Animais , Vetores Genéticos/metabolismo , Coração/diagnóstico por imagem , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Infarto do Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos , Ratos Wistar , Transdução de Sinais , Tomografia Computadorizada por Raios X , Regulação para Cima , Fator B de Crescimento do Endotélio Vascular/deficiência , Fator B de Crescimento do Endotélio Vascular/genética
16.
JACC Cardiovasc Imaging ; 4(12): 1294-301, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22172786

RESUMO

OBJECTIVES: This study investigated the effects of age, duration of a high-fat diet, and type 2 diabetes on atherosclerotic plaque development and uptake of (18)F-fluorodeoxyglucose ((18)F-FDG) in 2 mouse models. BACKGROUND: The animal's age and start time and duration of a high-fat diet have effects on plaque composition in atherosclerotic mice. METHODS: The aortas of atherosclerotic low-density lipoprotein receptor deficient mice expressing only apolipoprotein B100 (LDLR(-/-)ApoB(100/100)) and atherosclerotic and diabetic mice overexpressing insulin-like growth factor II (IGF-II/LDLR(-/-)ApoB(100/100)) were investigated at 4, 6, and 12 months of age and older after varying durations of high-fat diet. C57BL/6N mice on normal chow served as controls. Plaque size (intima-to-media ratio), macrophage density (Mac-3 staining), and plaque uptake of (18)F-FDG were studied by means of in vivo positron emission tomography/computed tomography by ex vivo autoradiography and by histological and immunohistochemical methods. RESULTS: From the ages of 4 to 6 months and 12 months and older, the plaque size increased and the macrophage density decreased. Compared with the controls, the in vivo imaging showed increased aortic (18)F-FDG uptake at 4 and 6 months, but not at 12 months and older. Autoradiography showed focal (18)F-FDG uptake in plaques at all time points (average plaque-to-normal vessel wall ratio: 2.4 ± 0.4, p < 0.001) with the highest uptake in plaques with high macrophage density. There were no differences in the plaque size, macrophage density, or uptake of (18)F-FDG between LDLR(-/-)ApoB(100/100) and IGF-II/LDLR(-/-)ApoB(100/100) mice at any time point. CONCLUSIONS: The 6-month-old LDLR(-/-)ApoB(100/100) and IGF-II/LDLR(-/-)ApoB(100/100) mice demonstrated highly inflamed, large, and extensive atherosclerotic plaques after 4 months of a high-fat diet, presenting a suitable model for studying the imaging of atherosclerotic plaque inflammation with (18)F-FDG. The presence of type 2 diabetes did not confound evaluation of plaque inflammation with (18)F-FDG.


Assuntos
Envelhecimento , Aterosclerose/diagnóstico por imagem , Aterosclerose/etiologia , Diabetes Mellitus Tipo 2/complicações , Dieta Hiperlipídica/efeitos adversos , Fluordesoxiglucose F18 , Imagem Multimodal , Placa Aterosclerótica/diagnóstico por imagem , Placa Aterosclerótica/etiologia , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Tomografia Computadorizada por Raios X , Fatores Etários , Animais , Aorta/diagnóstico por imagem , Aorta/patologia , Aortografia , Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Autorradiografia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Fluordesoxiglucose F18/farmacocinética , Imuno-Histoquímica , Macrófagos/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Placa Aterosclerótica/genética , Placa Aterosclerótica/metabolismo , Placa Aterosclerótica/patologia , Compostos Radiofarmacêuticos/farmacocinética , Receptor IGF Tipo 2/genética , Receptor IGF Tipo 2/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Risco
17.
Arterioscler Thromb Vasc Biol ; 31(5): 1011-5, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21372297

RESUMO

OBJECTIVE: Atherosclerotic plaques with large lipid cores and inflammation contain regions of hypoxia. We examined the uptake of 2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide ([18F]EF5), a specific marker of hypoxia labeled for positron emission tomography, in mouse atherosclerotic plaques. METHODS AND RESULTS: Atherosclerotic mice of 2 different genetic backgrounds (low-density lipoprotein receptor-/- apolipoprotein B100/100 and insulin-like growth factor II/low-density lipoprotein receptor-/- apolipoprotein B100/100) were first fed a Western diet to induce development of plaques with variable phenotypes and then injected with [18F]EF5. C57BL/6N mice served as controls. Aortas were dissected for biodistribution studies, autoradiography, histology, and immunohistochemistry. Uptake of [18F]EF5 was significantly higher in the aortas of mice with large atherosclerotic plaques than in the C57BL/6N controls. Furthermore, autoradiography demonstrated, on average, 2.0-fold higher [18F]EF5 uptake in atherosclerotic plaques than in the adjacent normal vessel wall. Hypoxia in plaques was verified by using an EF5 adduct-specific antibody and pimonidazole. The blood clearance of [18F]EF5 was slow, with blood radioactivity remaining relatively high up to 180 minutes after injection. CONCLUSIONS: Large atherosclerotic plaques in mice contained hypoxic areas and showed uptake of [18F]EF5. Despite its slow blood clearance, the high uptake of [18F]EF5 in plaques suggested that plaque hypoxia is a potential target for identifying high-risk plaques noninvasively.


Assuntos
Aorta/diagnóstico por imagem , Aterosclerose/diagnóstico por imagem , Etanidazol/análogos & derivados , Radioisótopos de Flúor , Hidrocarbonetos Fluorados , Hipóxia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Análise de Variância , Animais , Aorta/metabolismo , Aorta/patologia , Apolipoproteína B-100/deficiência , Apolipoproteína B-100/genética , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Autorradiografia , Modelos Animais de Doenças , Etanidazol/farmacocinética , Feminino , Radioisótopos de Flúor/farmacocinética , Genótipo , Hidrocarbonetos Fluorados/farmacocinética , Hipóxia/genética , Hipóxia/metabolismo , Hipóxia/patologia , Imuno-Histoquímica , Fator de Crescimento Insulin-Like II/deficiência , Fator de Crescimento Insulin-Like II/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Nitroimidazóis , Fenótipo , Compostos Radiofarmacêuticos/farmacocinética , Receptores de LDL/deficiência , Receptores de LDL/genética , Distribuição Tecidual
18.
J Nucl Med ; 51(5): 798-802, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20395326

RESUMO

UNLABELLED: The purpose of this study was to explore the feasibility of (11)C-choline in the assessment of the degree of inflammation in atherosclerotic plaques. METHODS: Uptake of (11)C-choline was studied ex vivo in tissue samples and aortic sections excised from 6 atherosclerotic mice deficient for both low-density lipoprotein receptor and apolipoprotein B48 (LDLR(-/-)ApoB(100/100)) and 5 control mice. The autoradiographs were compared with the immunohistology of the arterial sites. RESULTS: The uptake of (11)C-choline (percentage of the injected activity per gram of tissue) in the atherosclerotic aortas of the LDLR(-/-)ApoB(100/100) mice was significantly higher (1.9-fold, P = 0.0016) than that in the aortas of the control mice. The autoradiography analysis showed significantly higher uptake of (11)C-choline in the plaques than in healthy vessel wall (mean ratio, 2.3 +/- 0.6; P = 0.014), prominently in inflamed plaques, compared with noninflamed plaque areas. CONCLUSION: We observed a high (11)C-choline uptake in the aortic plaques of atherosclerotic mice. Our data suggest that macrophages may be responsible for the uptake of (11)C-choline in the plaques.


Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/metabolismo , Colina/farmacocinética , Compostos Radiofarmacêuticos/farmacocinética , Animais , Apolipoproteínas B/genética , Aterosclerose/genética , Criopreservação , Imuno-Histoquímica , Inflamação/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Cintilografia , Receptores de LDL/genética , Distribuição Tecidual
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA