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1.
Arterioscler Thromb Vasc Biol ; 41(9): e427-e439, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34261328

RESUMO

Objective: Atheromatous fibrous caps are produced by smooth muscle cells (SMCs) that are recruited to the subendothelial space. We tested whether the recruitment mechanisms are the same as in embryonic artery development, which relies prominently on Notch signaling to form the subendothelial medial SMC layers. Approach and Results: Notch elements were expressed in regions of fibrous cap in human and mouse plaques. To assess the causal role of Notch signaling in cap formation, we studied atherosclerosis in mice where the Notch pathway was inactivated in SMCs by conditional knockout of the essential effector transcription factor RBPJ (recombination signal-binding protein for immunoglobulin kappa J region). The recruitment of cap SMCs was significantly reduced without major effects on plaque size. Lineage tracing revealed the accumulation of SMC-derived plaque cells in the cap region was unaltered but that Notch-defective cells failed to re-acquire the SMC phenotype in the cap. Conversely, to analyze whether the loss of Notch signaling is required for SMC-derived cells to accumulate in atherogenesis, we studied atherosclerosis in mice with constitutive activation of Notch signaling in SMCs achieved by conditional expression of the Notch intracellular domain. Forced Notch signaling inhibited the ability of medial SMCs to contribute to plaque cells, including both cap SMCs and osteochondrogenic cells, and significantly reduced atherosclerosis development. Conclusions: Sequential loss and gain of Notch signaling is needed to build the cap SMC population. The shared mechanisms with embryonic arterial media assembly suggest that the cap forms as a neo-media that restores the connection between endothelium and subendothelial SMCs, transiently disrupted in early atherogenesis.


Assuntos
Aterosclerose/metabolismo , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Placa Aterosclerótica , Receptores Notch/metabolismo , Túnica Média/metabolismo , Actinas/genética , Actinas/metabolismo , Animais , Artérias/metabolismo , Artérias/patologia , Aterosclerose/genética , Aterosclerose/patologia , Linhagem da Célula , Células Cultivadas , Progressão da Doença , Fibrose , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/metabolismo , Proteína Jagged-1/genética , Proteína Jagged-1/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Fenótipo , Ratos , Receptores Notch/genética , Transdução de Sinais , Túnica Média/patologia
4.
J Am Coll Cardiol ; 77(5): 575-589, 2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33538256

RESUMO

BACKGROUND: The mechanisms by which hypertension accelerates coronary artery disease are poorly understood. Patients with hypertension often have confounding humoral changes, and to date, no experimental models have allowed analysis of the isolated effect of pressure on atherosclerosis in a setting that recapitulates the dimensions and biomechanics of human coronary arteries. OBJECTIVES: This study sought to analyze the effect of pressure on coronary atherosclerosis and explore the underlying mechanisms. METHODS: Using inflatable suprarenal aortic cuffs, we increased mean arterial pressure by >30 mm Hg in the cephalad body part of wild-type and hypercholesterolemic proprotein convertase subtilisin kexin type 9 (PCSK9)D374Y Yucatan minipigs for >1 year. Caudal pressures remained normal. RESULTS: Under hypercholesterolemic conditions in PCSK9D374Y transgenic minipigs, cephalad hypertension accelerated coronary atherosclerosis to almost 5-fold with consistent development of fibroatheromas that were sufficiently large to cause stenosis on computed tomography angiography. This was caused by local pressure forces, because vascular beds shielded from hypertension, but exposed to the same humoral factors, showed no changes in lesion formation. The same experiment was conducted under normocholesterolemic conditions in wild-type minipigs to examine the underlying mechanisms. Hypertension produced clear changes in the arterial proteome with increased abundance of mechanical strength proteins and reduced levels of infiltrating plasma macromolecules. This was paralleled by increased smooth muscle cells and increased intimal accumulation of low-density lipoproteins in the coronary arteries. CONCLUSIONS: Increased pressure per se facilitates coronary atherosclerosis. Our data indicate that restructuring of the artery to match increased tensile forces in hypertension alters the passage of macromolecules and leads to increased intimal accumulation of low-density lipoproteins.


Assuntos
Pressão Sanguínea/fisiologia , Doença da Artéria Coronariana/fisiopatologia , Hipertensão/fisiopatologia , Lipoproteínas LDL/sangue , Fluxo Sanguíneo Regional/fisiologia , Animais , Animais Geneticamente Modificados , Biomarcadores/sangue , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/etiologia , Modelos Animais de Doenças , Hipertensão/sangue , Hipertensão/complicações , Suínos , Porco Miniatura
5.
PLoS One ; 15(6): e0234131, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32502216

RESUMO

BACKGROUND: Low plasma testosterone, either spontaneous or as a result of androgen deprivation therapy for prostate cancer, is associated with an increased risk of cardiovascular events. The underlying mechanism in humans is not understood. Experimental studies in mice have shown that castration facilitates atherogenesis and may increase signs of plaque vulnerability. Pigs used for translational atherosclerosis research have frequently been castrated for practical or commercial reasons, but the effect of castration on atherosclerosis has never been systematically evaluated in pigs. OBJECTIVE: To study the effect of castration on atherosclerotic plaque burden and type in genetically modified minipigs with hypercholesterolemia. METHODS: Newborn male Yucatan minipigs with transgenic overexpression of a human gain-of-function mutant of proprotein convertase subtilisin/kexin type 9 were randomized to undergo orchiectomy (n = 8) or serve as controls (n = 6). Minipigs were started on high-fat diet at 3 months of age and the amount and composition of atherosclerotic lesions were analyzed at 12 months of age. Plasma lipid profiles and behavioral parameters were also assessed. RESULTS: Plasma lipids were slightly affected to a more atherogenic profile by orchiectomy, but atherosclerotic lesion size was unaltered in the LAD, thoracic aorta, abdominal aorta, and iliac arteries. The distribution of lesion types (xanthomas, pathological intimal thickening and fibroatheromas) were also not statistically different between groups in any of the examined vascular territories. The abdominal aorta developed the most advanced stages of disease with reproducible fibroatheroma formation, and here it was found that the area of necrotic core was significantly increased in orchiectomized pigs compared with controls. Orchiectomy also reduced aggressive behavior. CONCLUSIONS: Castration does not alter the burden of atherosclerosis in hypercholesterolemic Yucatan minipigs, but may increase necrotic core area in fibroatheromas.


Assuntos
Aterosclerose/patologia , Hipercolesterolemia/patologia , Animais , Animais Geneticamente Modificados , Aorta/patologia , Aterosclerose/complicações , Dieta Hiperlipídica , Modelos Animais de Doenças , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/genética , Artéria Ilíaca/patologia , Lipídeos/sangue , Masculino , Necrose , Orquiectomia , Pró-Proteína Convertase 9/genética , Pró-Proteína Convertase 9/metabolismo , Suínos , Porco Miniatura , Testosterona/sangue
8.
J Am Coll Cardiol ; 74(9): 1220-1232, 2019 09 03.
Artigo em Inglês | MEDLINE | ID: mdl-31466620

RESUMO

BACKGROUND: Arterial 18fluorodeoxyglucose (FDG) positron emission tomography (PET) is considered a measure of atherosclerotic plaque macrophages and is used for quantification of disease activity in clinical trials, but the distribution profile of FDG across macrophages and other arterial cells has not been fully clarified. OBJECTIVES: The purpose of this study was to analyze FDG uptake in different arterial tissues and their contribution to PET signal in normal and atherosclerotic arteries. METHODS: Wild-type and D374Y-PCSK9 transgenic Yucatan minipigs were fed a high-fat, high-cholesterol diet to induce atherosclerosis and subjected to a clinical FDG-PET and computed tomography scan protocol. Volumes of arterial media, intima/lesion, macrophage-rich, and hypoxic tissues were measured in serial histological sections. Distributions of FDG in macrophages and other arterial tissues were quantified using modeling of the in vivo PET signal. In separate transgenic minipigs, the intra-arterial localization of FDG was determined directly by autoradiography. RESULTS: Arterial FDG-PET signal appearance and intensity were similar to human imaging. The modeling approach showed high accuracy in describing the FDG-PET signal and revealed comparable FDG accumulation in macrophages and other arterial tissues, including medial smooth muscle cells. These findings were verified directly by autoradiography of normal and atherosclerotic arteries. CONCLUSIONS: FDG is taken up comparably in macrophage-rich and -poor arterial tissues in minipigs. This offers a mechanistic explanation to a growing number of observations in clinical imaging studies that have been difficult to reconcile with macrophage-selective FDG uptake.


Assuntos
Artérias/diagnóstico por imagem , Artérias/metabolismo , Aterosclerose/metabolismo , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Animais , Feminino , Masculino , Suínos , Porco Miniatura , Distribuição Tecidual
9.
Atherosclerosis ; 286: 156-162, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30871723

RESUMO

BACKGROUND AND AIMS: Type 1 diabetes accelerates the development of atherosclerotic cardiovascular diseases. Retention of low-density lipoprotein (LDL) in the arterial wall is a causal step in atherogenesis, but it is unknown whether diabetes alters the propensity of LDL for retention. The present study investigated whether LDL from type 1 diabetic and healthy non-diabetic subjects differed in their ability to bind to the arterial wall in a type 1 diabetic mouse model. METHODS: Fluorescently-labeled LDL obtained from type 1 diabetic patients or healthy controls was injected into mice with type 1 diabetes. The amount of retained LDL in the atherosclerosis-prone inner curvature of the aortic arch was quantified by fluorescence microscopy. Healthy control LDL was in vitro glycated, analyzed for protein glycation by LC-MS/MS, and tested for retention propensity. RESULTS: Retention of LDL from type 1 diabetic patients was 4.35-fold higher compared to LDL from nondiabetic subjects. Nuclear magnetic resonance (NMR) spectroscopy analysis of LDL revealed no differences in the concentration of the atherogenic small dense LDL between type 1 diabetic and non-diabetic subjects. In vitro glycation of LDL from a non-diabetic subject increased retention compared to non-glycated LDL. LC-MS/MS revealed four new glycated spots in the protein sequence of ApoB of in vitro glycated LDL. CONCLUSIONS: LDL from type 1 diabetic patients showed increased retention at atherosclerosis-prone sites in the arterial wall of diabetic mice. Glycation of LDL is one modification that may increase retention, but other, yet unknown, mechanisms are also likely to contribute.


Assuntos
Artérias/metabolismo , Aterosclerose/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Lipoproteínas LDL/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Humanos , Masculino , Camundongos
10.
Am J Nucl Med Mol Imaging ; 9(1): 1-11, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911433

RESUMO

Autoradiography using phosphor imaging screens is often used to characterize tissue distribution of positron emission tomography (PET) radiotracers. PET tracers emit positrons with limited penetration range, and valid quantitative autoradiography can therefore only be achieved in thin tissue slices. However, in some settings, quantitative tracer profiling in thick tissues is required. Our aim was to develop a reliable method for this purpose. In this paper, we present a method based on total intensity projections (TIPs) of PET and computed tomography (CT) images. We show theoretically and experimentally that tissue total activity and tissue volume maps can be derived from the TIPs of PET and CT images, respectively. We also show that these maps are free of signal displacement artifacts in the direction of projection. To demonstrate the utility of the approach, we obtain and compare TIP-based maps and autoradiography of ex-vivo atherosclerotic minipig aortas following in-vivo injection of 18F-fluorodeoxyglucose. We show that autoradiography of the thick aortas yields distorted results due to positron range effects, whereas TIP-mapping is free from such bias. The TIP-based maps may, thus, provide a low-resolution alternative to autoradiography, when tracer accumulation profiling in thick tissues is required.

11.
EuroIntervention ; 14(10): 1129-1135, 2018 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-29616625

RESUMO

AIMS: In vivo validation of coronary optical coherence tomography (OCT) against histology and the effects of plaque burden (PB) on plaque classification remain unreported. We aimed to investigate this in a porcine model with human-like coronary atherosclerosis. METHODS AND RESULTS: Five female Yucatan D374Y-PCSK9 transgenic hypercholesterolaemic minipigs were implanted with a coronary shear-modifying stent to induce advanced atherosclerosis. OCT frames (n=201) were obtained 34 weeks after implantation. Coronary arteries were perfusion-fixed, serially sectioned and co-registered with OCT using a validated algorithm. Lesions were adjudicated using the Virmani classification and PB assessed from histology. OCT had a high sensitivity, but modest specificity (92.9% and 74.6%), for identifying fibrous cap atheroma (FCA). The reduced specificity for OCT was due to misclassification of plaques with histologically defined pathological intimal thickening (PIT) as FCA (46.1% of the frames with histological PIT were misclassified). PIT lesions misclassified as FCA by OCT had a statistically higher PB than in other OCT frames (median 32.0% versus 13.4%; p<0.0001). Misclassification of PIT lesions by OCT occurred when PB exceeded approximately 20%. CONCLUSIONS: Compared with histology, in vivo OCT classification of FCA had high sensitivity but reduced specificity due to misclassification of PITs with high PB.


Assuntos
Doença da Artéria Coronariana , Placa Aterosclerótica , Animais , Vasos Coronários , Feminino , Humanos , Pró-Proteína Convertase 9 , Suínos , Tomografia de Coerência Óptica
12.
Circulation ; 138(3): 266-282, 2018 07 17.
Artigo em Inglês | MEDLINE | ID: mdl-29490993

RESUMO

BACKGROUND: Progerin, an aberrant protein that accumulates with age, causes the rare genetic disease Hutchinson-Gilford progeria syndrome (HGPS). Patients who have HGPS exhibit ubiquitous progerin expression, accelerated aging and atherosclerosis, and die in their early teens, mainly of myocardial infarction or stroke. The mechanisms underlying progerin-induced atherosclerosis remain unexplored, in part, because of the lack of appropriate animal models. METHODS: We generated an atherosclerosis-prone model of HGPS by crossing apolipoprotein E-deficient (Apoe-/-) mice with LmnaG609G/G609G mice ubiquitously expressing progerin. To induce progerin expression specifically in macrophages or vascular smooth muscle cells (VSMCs), we crossed Apoe-/-LmnaLCS/LCS mice with LysMCre and SM22αCre mice, respectively. Progerin expression was evaluated by polymerase chain reaction and immunofluorescence. Cardiovascular alterations were determined by immunofluorescence and histology in male mice fed normal chow or a high-fat diet. In vivo low-density lipoprotein retention was assessed by intravenous injection of fluorescently labeled human low-density lipoprotein. Cardiac electric defects were evaluated by electrocardiography. RESULTS: Apoe-/-LmnaG609G/G609G mice with ubiquitous progerin expression exhibited a premature aging phenotype that included failure to thrive and shortened survival. In addition, high-fat diet-fed Apoe-/-LmnaG609G/G609G mice developed a severe vascular pathology, including medial VSMC loss and lipid retention, adventitial fibrosis, and accelerated atherosclerosis, thus resembling most aspects of cardiovascular disease observed in patients with HGPS. The same vascular alterations were also observed in Apoe-/-LmnaLCS/LCSSM22αCre mice expressing progerin specifically in VSMCs, but not in Apoe-/-LmnaLCS/LCSLysMCre mice with macrophage-specific progerin expression. Moreover, Apoe-/-LmnaLCS/LCSSM22αCre mice had a shortened lifespan despite the lack of any overt aging phenotype. Aortas of ubiquitously and VSMC-specific progerin-expressing mice exhibited increased retention of fluorescently labeled human low-density lipoprotein, and atheromata in both models showed vulnerable plaque features. Immunohistopathological examination indicated that Apoe-/-LmnaLCS/LCSSM22αCre mice, unlike Apoe-/-LmnaG609G/G609G mice, die of atherosclerosis-related causes. CONCLUSIONS: We have generated the first mouse model of progerin-induced atherosclerosis acceleration, and demonstrate that restricting progerin expression to VSMCs is sufficient to accelerate atherosclerosis, trigger plaque vulnerability, and reduce lifespan. Our results identify progerin-induced VSMC death as a major factor triggering atherosclerosis and premature death in HGPS.


Assuntos
Aorta/patologia , Arteriosclerose/metabolismo , Lamina Tipo A/genética , Músculo Liso Vascular/metabolismo , Progéria/metabolismo , Animais , Arteriosclerose/genética , Senescência Celular , Modelos Animais de Doenças , Humanos , Lamina Tipo A/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Camundongos Transgênicos , Músculo Liso Vascular/patologia , Progéria/genética
13.
Cardiovasc Res ; 114(4): 492-500, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29293902

RESUMO

Advances in lineage-tracking techniques have provided new insights into the origins and fates of smooth muscle cells (SMCs) in atherosclerosis. Yet new tools present new challenges for data interpretation that require careful consideration of the strengths and weaknesses of the methods employed. At the same time, discoveries in other fields have introduced new perspectives on longstanding questions about steps in atherogenesis that remain poorly understood. In this article, we address both the challenges and opportunities for a better understanding of the mechanisms by which cells appearing as or deriving from SMCs accumulate in atherosclerosis.


Assuntos
Aterosclerose/patologia , Diferenciação Celular , Linhagem da Célula , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/patologia , Actinas/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/fisiopatologia , Biomarcadores/metabolismo , Diferenciação Celular/genética , Linhagem da Célula/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/metabolismo , Neovascularização Fisiológica , Fenótipo , Transdução de Sinais
14.
Sci Rep ; 7(1): 11670, 2017 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-28916789

RESUMO

Although A Disintegrin And Metalloproteinase 8 (ADAM8) is not crucial for tissue development and homeostasis, it has been implicated in various inflammatory diseases by regulating processes like immune cell recruitment and activation. ADAM8 expression has been associated with human atherosclerosis development and myocardial infarction, however a causal role of ADAM8 in atherosclerosis has not been investigated thus far. In this study, we examined the expression of ADAM8 in early and progressed human atherosclerotic lesions, in which ADAM8 was significantly upregulated in vulnerable lesions. In addition, ADAM8 expression was most prominent in the shoulder region of human atherosclerotic lesions, characterized by the abundance of foam cells. In mice, Adam8 was highly expressed in circulating neutrophils and in macrophages. Moreover, ADAM8 deficient mouse macrophages displayed reduced secretion of inflammatory mediators. Remarkably, however, neither hematopoietic nor whole-body ADAM8 deficiency in mice affected atherosclerotic lesion size. Additionally, except for an increase in granulocyte content in plaques of ADAM8 deficient mice, lesion morphology was unaffected. Taken together, whole body and hematopoietic ADAM8 does not contribute to advanced atherosclerotic plaque development, at least in female mice, although its expression might still be valuable as a diagnostic/prognostic biomarker to distinguish between stable and unstable lesions.


Assuntos
Proteínas ADAM/análise , Proteínas ADAM/deficiência , Aterosclerose/fisiopatologia , Proteínas de Membrana/análise , Proteínas de Membrana/deficiência , Placa Aterosclerótica/patologia , Animais , Antígenos CD , Artérias Carótidas/patologia , Feminino , Perfilação da Expressão Gênica , Humanos , Imuno-Histoquímica , Macrófagos/química , Camundongos Endogâmicos C57BL , Camundongos Knockout
17.
Atherosclerosis ; 263: 7-14, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28550710

RESUMO

BACKGROUND AND AIMS: Individuals with type 1 diabetes mellitus are at high risk of developing atherosclerotic cardiovascular disease, but the underlying mechanisms by which type 1 diabetes accelerates atherosclerosis remain unknown. Increased retention of low-density lipoprotein (LDL) in atherosclerosis-prone sites of the diabetic vascular wall has been suggested, but direct evidence is lacking. In the present study, we investigated whether retention of LDL is increased in atherosclerotic-prone areas using a murine model of type 1 diabetes. METHODS: Fluorescently-labeled human LDL from healthy non-diabetic individuals was injected into diabetic Ins2Akita mice and non-diabetic, wild-type littermates. The amount of retained LDL after 24 h was quantified by fluorescence microscopy of cryosections and by scans of en face preparations. Vascular gene expression in the inner curvature of the aortic arch was analyzed by microarray and quantitative polymerase chain reaction. RESULTS: LDL retention was readily detected in atherosclerosis-prone areas of the aortic arch being located in both intimal and medial layers. Quantitative microscopy revealed 8.1-fold more retained LDL in type 1 diabetic mice compared to wild-type mice. These findings were confirmed in independent experiments using near-infrared scanning of en face preparations of the aorta. Diabetic status did not affect arterial expression of genes known to be involved in LDL retention. CONCLUSIONS: Type 1 diabetes increases the ability of the vascular wall to retain LDL in mice. These changes could contribute to the increased atherosclerotic burden seen in type 1 diabetic patients.


Assuntos
Aorta/metabolismo , Aterosclerose/complicações , Aterosclerose/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/metabolismo , Lipoproteínas LDL/metabolismo , Animais , Aorta Torácica/metabolismo , Artérias/metabolismo , Glicemia/química , Espessura Intima-Media Carotídea , Modelos Animais de Doenças , Feminino , Corantes Fluorescentes/química , Perfilação da Expressão Gênica , Humanos , Hipercolesterolemia/metabolismo , Hiperglicemia/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência , Mutação , Análise Serial de Tecidos
18.
Anim Reprod Sci ; 178: 40-49, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28126267

RESUMO

Porcine somatic cell nuclear transfer (SCNT) has been used extensively to create genetically modified pigs, but the efficiency of the methodology is still low. It has been hypothesized that pluripotent or multipotent stem cells might result in increased SCNT efficacy as these cells are closer than somatic cells to the epigenetic state found in the blastomeres and therefore need less reprogramming. Our group has worked with porcine SCNT during the last 20 years and here we describe our experience with SCNT of 3 different stem cell lines. The porcine stem cells used were: Induced pluripotent stem cells (iPSCs) created by lentiviral doxycycline-dependent reprogramming and cultered with a GSK3ß- and MEK-inhibitor (2i) and leukemia inhibitor factor (LIF) (2i LIF DOX-iPSCs), iPSCs created by a plasmid-based reprogramming and cultured with 2i and fibroblast growth factor (FGF) (2i FGF Pl-iPSCs) and embryonic germ cells (EGCs), which have earlier been characterized as being multipotent. The SCNT efficiencies of these stem cell lines were compared with that of the two fibroblast cell lines from which the iPSC lines were derived. The blastocyst rates for the 2i LIF DOX-iPSCs were 14.7%, for the 2i FGF Pl-iPSC 10.1%, and for the EGCs 34.5% compared with the fibroblast lines yielding 36.7% and 25.2%. The fibroblast- and EGC-derived embryos were used for embryo transfer and produced live offspring at similar low rates of efficiency (3.2 and 4.0%, respectively) and with several instances of malformations. In conclusion, potentially pluripotent porcine stem cells resulted in lower rates of embryonic development upon SCNT than multipotent stem cells and differentiated somatic cells.


Assuntos
Clonagem de Organismos/veterinária , Técnicas de Transferência Nuclear/veterinária , Células-Tronco Pluripotentes/fisiologia , Suínos/genética , Suínos/fisiologia , Animais , Animais Geneticamente Modificados , Linhagem Celular , Reprogramação Celular , Clonagem de Organismos/métodos , Transferência Embrionária/veterinária , Embrião de Mamíferos/fisiologia , Desenvolvimento Embrionário , Feminino , Fibroblastos/fisiologia , Proteínas de Fluorescência Verde , Masculino , Gravidez
19.
JACC Basic Transl Sci ; 2(5): 591-600, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30062172

RESUMO

Deficiency of apolipoprotein E (APOE) causes familial dysbetalipoproteinemia in humans resulting in a higher risk of atherosclerotic disease. In mice, APOE deficiency results in a severe atherosclerosis phenotype, but it is unknown to what extent this is unique to mice. In this study, APOE was targeted in Yucatan minipigs. APOE-/- minipigs displayed increased plasma cholesterol and accumulation of apolipoprotein B-48-containing chylomicron remnants on low-fat diet, which was significantly accentuated upon feeding a high-fat, high-cholesterol diet. APOE-/- minipigs displayed accelerated progressive atherosclerosis but not xanthoma formation. This indicates that remnant lipoproteinemia does not induce early lesions but is atherogenic in pre-existing atherosclerosis.

20.
J Am Coll Cardiol ; 68(25): 2794-2796, 2016 12 27.
Artigo em Inglês | MEDLINE | ID: mdl-28007142
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