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1.
Patient Prefer Adherence ; 18: 1095-1105, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38854479

RESUMEN

Purpose: Stroke is a major disease endangering the health of Chinese people, and patients need to rely on the care of family members, which brings heavy caregiving burdens and pressures to caregivers and families, thus disrupting the stable family structure. In view of this, this study was to analyse the current status of family resilience among caregivers of stroke patients in Chinese nuclear families, and to explore the correlation and mechanism of action among perceived stress, illness uncertainty and family resilience. Patients and Methods: This study used a cross-sectional research design. A total of 350 carers of stroke patients in nuclear families from four tertiary hospitals in Suzhou City, Jiangsu Province, China were selected by convenience sampling method and assessed by using demographic questionnaires, the Chinese Perceived Stress Scale (CPSS), the Parental Perceptions of Uncertainty Scale-Family (PPUS-FM), and a short Chinese version of the Family Resilience Assessment Scale (FRAS-C). Based on the above data, structural equation model was used to test the mediating role of perceived stress between illness uncertainty and family resilience. Results: Family resilience among caregivers of stroke patients in nuclear families was at the medium lower level, illness uncertainty was at the medium level, and perceived stress was at the relatively high level. Illness uncertainty was positively correlated with perceived stress (P<0.01) and negatively correlated with family resilience (P<0.01). Illness uncertainty directly predicted family resilience (ß = -0.516, p < 0.05). And the pathway between illness uncertainty and family resilience was partially mediated by perceived stress (Effect= -0.091, 95% CI [-0.141, -0.055]). Conclusion: Healthcare professionals should pay adequate attention to the level of illness uncertainty and perceived stress among carers of stroke patients, with the need to take measures to reduce carers' illness uncertainty and perceived stress in order to improve family resilience.

2.
PLoS One ; 19(5): e0303610, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38758931

RESUMEN

We have previously shown that polygenic risk scores (PRS) can improve risk stratification of peripheral artery disease (PAD) in a large, retrospective cohort. Here, we evaluate the potential of PRS in improving the detection of PAD and prediction of major adverse cardiovascular and cerebrovascular events (MACCE) and adverse events (AE) in an institutional patient cohort. We created a cohort of 278 patients (52 cases and 226 controls) and fit a PAD-specific PRS based on the weighted sum of risk alleles. We built traditional clinical risk models and machine learning (ML) models using clinical and genetic variables to detect PAD, MACCE, and AE. The models' performances were measured using the area under the curve (AUC), net reclassification index (NRI), integrated discrimination improvement (IDI), and Brier score. We also evaluated the clinical utility of our PAD model using decision curve analysis (DCA). We found a modest, but not statistically significant improvement in the PAD detection model's performance with the inclusion of PRS from 0.902 (95% CI: 0.846-0.957) (clinical variables only) to 0.909 (95% CI: 0.856-0.961) (clinical variables with PRS). The PRS inclusion significantly improved risk re-classification of PAD with an NRI of 0.07 (95% CI: 0.002-0.137), p = 0.04. For our ML model predicting MACCE, the addition of PRS did not significantly improve the AUC, however, NRI analysis demonstrated significant improvement in risk re-classification (p = 2e-05). Decision curve analysis showed higher net benefit of our combined PRS-clinical model across all thresholds of PAD detection. Including PRS to a clinical PAD-risk model was associated with improvement in risk stratification and clinical utility, although we did not see a significant change in AUC. This result underscores the potential clinical utility of incorporating PRS data into clinical risk models for prevalent PAD and the need for use of evaluation metrics that can discern the clinical impact of using new biomarkers in smaller populations.


Asunto(s)
Enfermedad Arterial Periférica , Humanos , Enfermedad Arterial Periférica/genética , Enfermedad Arterial Periférica/diagnóstico , Femenino , Masculino , Anciano , Persona de Mediana Edad , Medición de Riesgo/métodos , Factores de Riesgo , Aprendizaje Automático , Enfermedades Cardiovasculares/genética , Enfermedades Cardiovasculares/diagnóstico , Estudios Retrospectivos , Herencia Multifactorial/genética , Estudios de Casos y Controles , Área Bajo la Curva , Puntuación de Riesgo Genético
3.
Nat Cardiovasc Res ; 1(3): 253-262, 2022 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-35990913

RESUMEN

The pleiotropic benefits of statins may result from their impact on vascular inflammation. The molecular process underlying this phenomenon is not fully elucidated. Here, RNA sequencing designed to investigate gene expression patterns following CD47-SIRPα inhibition identifies a link between statins, efferocytosis, and vascular inflammation. In vivo and in vitro studies provide evidence that statins augment programmed cell removal by inhibiting the nuclear translocation of NFκB1 p50 and suppressing the expression of the critical 'don't eat me' molecule, CD47. Statins amplify the phagocytic capacity of macrophages, and thus the anti-atherosclerotic effects of CD47-SIRPα blockade, in an additive manner. Analyses of clinical biobank specimens suggest a similar link between statins and CD47 expression in humans, highlighting the potential translational implications. Taken together, our findings identify efferocytosis and CD47 as pivotal mediators of statin pleiotropy. In turn, statins amplify the anti-atherosclerotic effects of pro-phagocytic therapies independently of any lipid-lowering effect.

4.
Arterioscler Thromb Vasc Biol ; 42(1): e1-e9, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34758632

RESUMEN

OBJECTIVE: Antibody blockade of the "do not eat me" signal CD47 (cluster of differentiation 47) enhances efferocytosis and reduces lesion size and necrotic core formation in murine atherosclerosis. TNF (Tumor necrosis factor)-α expression directly enhances CD47 expression, and elevated TNF-α is observed in the absence of the proefferocytosis receptor LRP1 (low-density lipoprotein receptor-related protein 1), a regulator of atherogenesis and inflammation. Thus, we tested the hypothesis that CD47 blockade requires the presence of macrophage LRP1 to enhance efferocytosis, temper TNF-α-dependent inflammation, and limit atherosclerosis. Approach and Results: Mice lacking systemic apoE (apoE-/-), alone or in combination with the loss of macrophage LRP1 (double knockout), were fed a Western-type diet for 12 weeks while receiving anti-CD47 antibody (anti-CD47) or IgG every other day. In apoE-/- mice, treatment with anti-CD47 reduced lesion size by 25.4%, decreased necrotic core area by 34.5%, and decreased the ratio of free:macrophage-associated apoptotic bodies by 47.6% compared with IgG controls (P<0.05), confirming previous reports. Double knockout mice treated with anti-CD47 showed no differences in lesion size, necrotic core area, or the ratio of free:macrophage-associated apoptotic bodies compared with IgG controls. In vitro efferocytosis was 30% higher when apoE-/- phagocytes were incubated with anti-CD47 compared with IgG controls (P<0.05); however, anti-CD47 had no effect on efferocytosis in double knockout phagocytes. Analyses of mRNA and protein showed increased CD47 expression in anti-inflammatory IL (interleukin)-4 treated LRP1-/- macrophages compared with wild type, but no differences were observed in inflammatory lipopolysaccharide-treated macrophages. CONCLUSIONS: The proefferocytosis receptor LRP1 in macrophages is necessary for anti-CD47 blockade to enhance efferocytosis, limit atherogenesis, and decrease necrotic core formation in the apoE-/- model of atherosclerosis.


Asunto(s)
Antiinflamatorios/farmacología , Anticuerpos Bloqueadores/farmacología , Aorta/efectos de los fármacos , Enfermedades de la Aorta/prevención & control , Aterosclerosis/prevención & control , Antígeno CD47/antagonistas & inhibidores , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Macrófagos/efectos de los fármacos , Fagocitosis/efectos de los fármacos , Animales , Aorta/inmunología , Aorta/metabolismo , Aorta/patología , Enfermedades de la Aorta/inmunología , Enfermedades de la Aorta/metabolismo , Enfermedades de la Aorta/patología , Aterosclerosis/inmunología , Aterosclerosis/metabolismo , Aterosclerosis/patología , Antígeno CD47/inmunología , Antígeno CD47/metabolismo , Células Cultivadas , Modelos Animales de Enfermedad , Proteína 1 Relacionada con Receptor de Lipoproteína de Baja Densidad/genética , Macrófagos/inmunología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Necrosis , Placa Aterosclerótica , Factor de Necrosis Tumoral alfa/metabolismo
5.
Cardiovasc Res ; 118(13): 2792-2804, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-34849613

RESUMEN

AIMS: De-differentiation and activation of pro-inflammatory pathways are key transitions vascular smooth muscle cells (SMCs) make during atherogenesis. Here, we explored the upstream regulators of this 'atherogenic transition'. METHODS AND RESULTS: Genome-wide sequencing studies, including Assay for Transposase-Accessible Chromatin using sequencing and RNA-seq, were performed on cells isolated from both murine SMC-lineage-tracing models of atherosclerosis and human atherosclerotic lesions. At the bulk level, alterations in chromatin accessibility were associated with the atherogenic transitioning of lesional SMCs, especially in relation to genes that govern differentiation status and complement-dependent inflammation. Using computational biology, we observed that a transcription factor previously related to coronary artery disease, Activating transcription factor 3 (ATF3), was predicted to be an upstream regulator of genes altered during the transition. At the single-cell level, our results indicated that ATF3 is a key repressor of SMC transitioning towards the subset of cells that promote vascular inflammation by activating the complement cascade. The expression of ATF3 and complement component C3 was negatively correlated in SMCs from human atherosclerotic lesions, suggesting translational relevance. Phenome-wide association studies indicated that genetic variation that results in reduced expression of ATF3 is correlated with an increased risk for atherosclerosis, and the expression of ATF3 was significantly down-regulated in humans with advanced vascular disease. CONCLUSION: Our study indicates that the plasticity of atherosclerotic SMCs may in part be explained by dynamic changes in their chromatin architecture, which in turn may contribute to their maladaptive response to inflammation-induced stress.


Asunto(s)
Aterosclerosis , Músculo Liso Vascular , Humanos , Ratones , Animales , Músculo Liso Vascular/metabolismo , Cromatina/genética , Factor de Transcripción Activador 3/genética , Factor de Transcripción Activador 3/metabolismo , Miocitos del Músculo Liso/metabolismo , Aterosclerosis/metabolismo , Inflamación/metabolismo
6.
Cardiovasc Res ; 117(14): 2767-2780, 2021 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33471078

RESUMEN

AIMS: Atherosclerotic cerebrovascular disease underlies the majority of ischaemic strokes and is a major cause of death and disability. While plaque burden is a predictor of adverse outcomes, plaque vulnerability is increasingly recognized as a driver of lesion rupture and risk for clinical events. Defining the molecular regulators of carotid instability could inform the development of new biomarkers and/or translational targets for at-risk individuals. METHODS AND RESULTS: Using two independent human endarterectomy biobanks, we found that the understudied glycoprotein, chitinase 3 like 1 (CHI3L1), is up-regulated in patients with carotid disease compared to healthy controls. Further, CHI3L1 levels were found to stratify individuals based on symptomatology and histopathological evidence of an unstable fibrous cap. Gain- and loss-of-function studies in cultured human carotid artery smooth muscle cells (SMCs) showed that CHI3L1 prevents a number of maladaptive changes in that cell type, including phenotype switching towards a synthetic and hyperproliferative state. Using two murine models of carotid remodelling and lesion vulnerability, we found that knockdown of Chil1 resulted in larger neointimal lesions comprised by de-differentiated SMCs that failed to invest within and stabilize the fibrous cap. Exploratory mechanistic studies identified alterations in potential downstream regulatory genes, including large tumour suppressor kinase 2 (LATS2), which mediates macrophage marker and inflammatory cytokine expression on SMCs, and may explain how CHI3L1 modulates cellular plasticity. CONCLUSION: CHI3L1 is up-regulated in humans with carotid artery disease and appears to be a strong mediator of plaque vulnerability. Mechanistic studies suggest this change may be a context-dependent adaptive response meant to maintain vascular SMCs in a differentiated state and to prevent rupture of the fibrous cap. Part of this effect may be mediated through downstream suppression of LATS2. Future studies should determine how these changes occur at the molecular level, and whether this gene can be targeted as a novel translational therapy for subjects at risk of stroke.


Asunto(s)
Enfermedades de las Arterias Carótidas/enzimología , Diferenciación Celular , Proteína 1 Similar a Quitinasa-3/metabolismo , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , Placa Aterosclerótica , Animales , Arterias Carótidas/enzimología , Arterias Carótidas/patología , Arterias Carótidas/fisiopatología , Enfermedades de las Arterias Carótidas/genética , Enfermedades de las Arterias Carótidas/patología , Enfermedades de las Arterias Carótidas/fisiopatología , Células Cultivadas , Proteína 1 Similar a Quitinasa-3/genética , Modelos Animales de Enfermedad , Fibrosis , Humanos , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Músculo Liso Vascular/patología , Músculo Liso Vascular/fisiopatología , Miocitos del Músculo Liso/patología , Neointima , Fenotipo , Rotura Espontánea , Remodelación Vascular
7.
Arterioscler Thromb Vasc Biol ; 40(12): 2821-2828, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33086865

RESUMEN

OBJECTIVE: This study sought to determine whether 18F-fluorodeoxyglucose-positron emission tomography/computed tomography could be applied to a murine model of advanced atherosclerotic plaque vulnerability to detect response to therapeutic intervention and changes in lesion stability. Approach and Results: To analyze plaques susceptible to rupture, we fed ApoE-/- mice a high-fat diet and induced vulnerable lesions by cast placement over the carotid artery. After 9 weeks of treatment with orthogonal therapeutic agents (including lipid-lowering and proefferocytic therapies), we assessed vascular inflammation and several features of plaque vulnerability by 18F-fluorodeoxyglucose-positron emission tomography/computed tomography and histopathology, respectively. We observed that 18F-fluorodeoxyglucose-positron emission tomography/computed tomography had the capacity to resolve histopathologically proven changes in plaque stability after treatment. Moreover, mean target-to-background ratios correlated with multiple characteristics of lesion instability, including the corrected vulnerability index. CONCLUSIONS: These results suggest that the application of noninvasive 18F-fluorodeoxyglucose-positron emission tomography/computed tomography to a murine model can allow for the identification of vulnerable atherosclerotic plaques and their response to therapeutic intervention. This approach may prove useful as a drug discovery and prioritization method.


Asunto(s)
Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Arteria Carótida Común/diagnóstico por imagen , Fluorodesoxiglucosa F18/administración & dosificación , Placa Aterosclerótica , Tomografía Computarizada por Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Animales , Anticuerpos Bloqueadores/farmacología , Atorvastatina/farmacología , Antígeno CD47/antagonistas & inhibidores , Enfermedades de las Arterias Carótidas/tratamiento farmacológico , Enfermedades de las Arterias Carótidas/patología , Arteria Carótida Común/efectos de los fármacos , Arteria Carótida Común/patología , Modelos Animales de Enfermedad , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados para ApoE , Valor Predictivo de las Pruebas , Rotura Espontánea
8.
Proc Natl Acad Sci U S A ; 117(27): 15818-15826, 2020 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-32541024

RESUMEN

Atherosclerosis is the process underlying heart attack and stroke. Despite decades of research, its pathogenesis remains unclear. Dogma suggests that atherosclerotic plaques expand primarily via the accumulation of cholesterol and inflammatory cells. However, recent evidence suggests that a substantial portion of the plaque may arise from a subset of "dedifferentiated" vascular smooth muscle cells (SMCs) which proliferate in a clonal fashion. Herein we use multicolor lineage-tracing models to confirm that the mature SMC can give rise to a hyperproliferative cell which appears to promote inflammation via elaboration of complement-dependent anaphylatoxins. Despite being extensively opsonized with prophagocytic complement fragments, we find that this cell also escapes immune surveillance by neighboring macrophages, thereby exacerbating its relative survival advantage. Mechanistic studies indicate this phenomenon results from a generalized opsonin-sensing defect acquired by macrophages during polarization. This defect coincides with the noncanonical up-regulation of so-called don't eat me molecules on inflamed phagocytes, which reduces their capacity for programmed cell removal (PrCR). Knockdown or knockout of the key antiphagocytic molecule CD47 restores the ability of macrophages to sense and clear opsonized targets in vitro, allowing for potent and targeted suppression of clonal SMC expansion in the plaque in vivo. Because integrated clinical and genomic analyses indicate that similar pathways are active in humans with cardiovascular disease, these studies suggest that the clonally expanding SMC may represent a translational target for treating atherosclerosis.


Asunto(s)
Aterosclerosis/metabolismo , Clonación Molecular , Activación de Complemento , Miocitos del Músculo Liso/metabolismo , Fagocitosis/fisiología , Animales , Antígeno CD47/metabolismo , Linaje de la Célula , Proliferación Celular , Complemento C3/genética , Complemento C3/metabolismo , Femenino , Humanos , Inflamación , Macrófagos/metabolismo , Masculino , Ratones Noqueados para ApoE , Miocitos del Músculo Liso/citología , Placa Aterosclerótica/metabolismo , Análisis de Secuencia de ARN , Regulación hacia Arriba
10.
Nat Nanotechnol ; 15(2): 154-161, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31988506

RESUMEN

Atherosclerosis is the process that underlies heart attack and stroke. A characteristic feature of the atherosclerotic plaque is the accumulation of apoptotic cells in the necrotic core. Prophagocytic antibody-based therapies are currently being explored to stimulate the phagocytic clearance of apoptotic cells; however, these therapies can cause off-target clearance of healthy tissues, which leads to toxicities such as anaemia. Here we developed a macrophage-specific nanotherapy based on single-walled carbon nanotubes loaded with a chemical inhibitor of the antiphagocytic CD47-SIRPα signalling axis. We demonstrate that these single-walled carbon nanotubes accumulate within the atherosclerotic plaque, reactivate lesional phagocytosis and reduce the plaque burden in atheroprone apolipoprotein-E-deficient mice without compromising safety, and thereby overcome a key translational barrier for this class of drugs. Single-cell RNA sequencing analysis reveals that prophagocytic single-walled carbon nanotubes decrease the expression of inflammatory genes linked to cytokine and chemokine pathways in lesional macrophages, which demonstrates the potential of 'Trojan horse' nanoparticles to prevent atherosclerotic cardiovascular disease.


Asunto(s)
Aterosclerosis/metabolismo , Macrófagos , Nanotubos de Carbono , Fagocitosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Animales , Antígeno CD47/metabolismo , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/farmacología , Modelos Animales de Enfermedad , Femenino , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Transgénicos , Nanomedicina/métodos , Proteína Tirosina Fosfatasa no Receptora Tipo 6/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Receptores Inmunológicos/metabolismo
11.
Arterioscler Thromb Vasc Biol ; 39(4): 635-646, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30786744

RESUMEN

Nanoparticles promise to advance strategies to treat vascular disease. Since being harnessed by the cancer field to deliver safer and more effective chemotherapeutics, nanoparticles have been translated into applications for cardiovascular disease. Systemic exposure and drug-drug interactions remain a concern for nearly all cardiovascular therapies, including statins, antithrombotic, and thrombolytic agents. Moreover, off-target effects and poor bioavailability have limited the development of completely new approaches to treat vascular disease. Through the rational design of nanoparticles, nano-based delivery systems enable more efficient delivery of a drug to its therapeutic target or even directly to the diseased site, overcoming biological barriers and enhancing a drug's therapeutic index. In addition, advances in molecular imaging have led to the development of theranostic nanoparticles that may simultaneously act as carriers of both therapeutic and imaging payloads. The following is a summary of nanoparticle therapy for atherosclerosis, thrombosis, and restenosis and an overview of recent major advances in the targeted treatment of vascular disease.


Asunto(s)
Fármacos Cardiovasculares/administración & dosificación , Portadores de Fármacos/administración & dosificación , Nanopartículas/administración & dosificación , Enfermedades Vasculares/tratamiento farmacológico , Animales , Quimiotaxis de Leucocito/efectos de los fármacos , Colesterol/metabolismo , Evaluación Preclínica de Medicamentos , Predicción , Humanos , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Ratones , Neointima/tratamiento farmacológico , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/fisiopatología , Placa Aterosclerótica/fisiopatología , Interferencia de ARN , ARN Interferente Pequeño/farmacología , Trombosis/tratamiento farmacológico
13.
Am J Cardiovasc Dis ; 7(3): 72-82, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-28695053

RESUMEN

When challenged by hemodynamic stress, aging hearts respond differently to young hearts. Preclinical models of heart disease should take into account the effects of age. However, in the transverse aortic constriction (TAC) model of pressure-overload cardiomyopathy, the larger aorta of aging mice has not previously been taken into account. First, we studied the aortic size in mice, and found that the aortic cross-sectional area (CSA) is 28% larger in aging mice than in young adult mice (P=0.001). We then performed TAC to make the same proportional reduction in CSA in young and aging mice. This produced the same pressure gradient across the constriction and the same rise in B-type natriuretic peptide expression. Young mice showed acute deterioration in systolic function assessed by pressure-volume loops, progressive LV remodeling on echocardiography, and a 50% mortality at 12 weeks post-TAC. In contrast, aging mice showed no acute deterioration in systolic function, much less ventricular remodeling and were protected from death. Aging mice also showed significantly increased levels of matrix metalloproteinase-3 (MMP-3; 3.2 fold increase, P<0.001) and MMP-12 (1.5-fold increase, P<0.001), which were not seen in young mice. Expression of tissue inhibitor of MMP-1 (TIMP-1) increased 8.6-fold in aging hearts vs 4.3-fold in young hearts (P<0.01). In conclusion, following size-appropriate TAC, aging mice exhibit less LV remodeling and lower mortality than young adult mice. This is associated with induction of protective ECM changes.

14.
JACC Basic Transl Sci ; 2(2): 209-211, 2017 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-30167568

RESUMEN

It is now known that the internalization and transcytosis of low density lipoprotein (LDL) in the vessel wall occurs through molecular pathways independent of the LDL receptor. In a study recently published in Nature Communications, investigators cross-referenced results from a genome-wide ribonucleic acid interference screen with targets identified in publicly-available genome-wide association studies datasets to identify activin-like kinase 1 as a novel driver of this process. This approach has relevance to the field of atherosclerosis, and could be used as a model for the prioritization of future "hits" in large-scale genomic screens.

15.
Nature ; 536(7614): 86-90, 2016 08 04.
Artículo en Inglés | MEDLINE | ID: mdl-27437576

RESUMEN

Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.


Asunto(s)
Anticuerpos Bloqueadores/inmunología , Anticuerpos Bloqueadores/farmacología , Aterosclerosis/prevención & control , Antígeno CD47/inmunología , Fagocitosis/efectos de los fármacos , Animales , Apoptosis , Aterosclerosis/metabolismo , Aterosclerosis/patología , Aterosclerosis/terapia , Antígeno CD47/biosíntesis , Antígeno CD47/metabolismo , Arterias Carótidas/patología , Vasos Coronarios/patología , Modelos Animales de Enfermedad , Femenino , Humanos , Masculino , Ratones , FN-kappa B/metabolismo , Biosíntesis de Proteínas , Factor de Necrosis Tumoral alfa/metabolismo , Regulación hacia Arriba
16.
Biomaterials ; 89: 136-47, 2016 May.
Artículo en Inglés | MEDLINE | ID: mdl-26967648

RESUMEN

A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo. The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1(+)/CD45(-)/CD34(+)/CD44(+) cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF165, and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb.


Asunto(s)
Materiales Biocompatibles/metabolismo , Ácido Hialurónico/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Metaloproteinasa 13 de la Matriz/metabolismo , Trasplante de Células Madre , Animales , Materiales Biocompatibles/química , Adhesión Celular , Proliferación Celular , Células Cultivadas , Ácido Hialurónico/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Metaloproteinasa 13 de la Matriz/química , Ratones , Ratones Endogámicos C57BL , Miocardio/citología , Neovascularización Fisiológica , Péptidos/química , Péptidos/metabolismo , Trasplante de Células Madre/métodos , Células Madre/citología , Células Madre/metabolismo , Andamios del Tejido/química
17.
Circ Res ; 118(2): 230-40, 2016 Jan 22.
Artículo en Inglés | MEDLINE | ID: mdl-26596284

RESUMEN

RATIONALE: Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown. OBJECTIVE: To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism. METHODS AND RESULTS: Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor ß (TGFß) signaling in cultured cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient cells, as well as TGFß1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7, which promotes downstream TGFß activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGFß1-induced-1, which is a TGFß-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro. CONCLUSIONS: These results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGFß signaling and hypoxic neovessel maturation.


Asunto(s)
Aterosclerosis/enzimología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/metabolismo , Músculo Esquelético/irrigación sanguínea , Músculo Liso Vascular/enzimología , Miocitos del Músculo Liso/enzimología , Neovascularización Fisiológica , Transducción de Señal , Factor de Crecimiento Transformador beta1/metabolismo , Animales , Aterosclerosis/genética , Aterosclerosis/mortalidad , Aterosclerosis/patología , Arterias Carótidas/enzimología , Arterias Carótidas/patología , Hipoxia de la Célula , Células Cultivadas , Cromosomas Humanos Par 9 , Vasos Coronarios/enzimología , Vasos Coronarios/patología , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/deficiencia , Inhibidor p15 de las Quinasas Dependientes de la Ciclina/genética , Modelos Animales de Enfermedad , Femenino , Predisposición Genética a la Enfermedad , Miembro Posterior , Humanos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Músculo Liso Vascular/fisiopatología , Neovascularización Patológica , Fenotipo , Interferencia de ARN , Proteína smad7/metabolismo , Factores de Tiempo , Transfección , Factor de Crecimiento Transformador beta1/genética
18.
PLoS One ; 10(7): e0131123, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26230835

RESUMEN

BACKGROUND: We previously reported the generation of a reporter line of human embryonic stem cells (hESCs) with enhanced green fluorescent protein (eGFP) expression driven by the α-myosin heavy chain (αMHC) promoter. The GFP+/αMHC+ cells derived from this cell line behave as multipotent, human myocardial precursors (hMPs) in vitro. In this study, we evaluated the therapeutic effects of GFP+/αMHC+ cells isolated from the reporter line in a mouse model of myocardial infarction (MI). METHODS: MI was generated in immunodeficient mice. hMPs were injected into murine infarcted hearts under ultrasound guidance at 3 days post-MI. Human fetal skin fibroblasts (hFFs) were injected as control. Cardiac function was evaluated by echocardiography. Infarct size, angiogenesis, apoptosis, cell fate, and teratoma formation were analyzed by immunohistochemical staining. RESULTS: Compared with control, hMPs resulted in improvement of cardiac function post-MI with smaller infarct size, induced endogenous angiogenesis, and reduced apoptosis of host cardiomyocytes at the peri-infarct zone at 28 days post-MI. CONCLUSION: Intramyocardial injection of hMPs improved cardiac function post-MI. The engraftment rate of these cells in the myocardium post-MI was low, suggesting that the majority of effect occurs via paracrine mechanisms.


Asunto(s)
Tratamiento Basado en Trasplante de Células y Tejidos/métodos , Células Madre Embrionarias/trasplante , Células Madre Multipotentes/trasplante , Infarto del Miocardio/terapia , Miocitos Cardíacos/citología , Animales , Apoptosis/fisiología , Células Cultivadas , Ecocardiografía , Femenino , Proteínas Fluorescentes Verdes/genética , Corazón/fisiopatología , Pruebas de Función Cardíaca , Humanos , Ratones , Ratones SCID , Neovascularización Fisiológica
19.
J Control Release ; 209: 308-16, 2015 Jul 10.
Artículo en Inglés | MEDLINE | ID: mdl-25931306

RESUMEN

Growth factors are critical for regulating and inducing various stem cell functions. To study the effects of growth factor delivery kinetics and presentation on stem cell fate, we developed a series of heparin-containing hyaluronic acid (HyA)-based hydrogels with various degrees of growth factor affinity and retention. To characterize this system, we investigated the effect of heparin molecular weight, fractionation, and relative concentration on the loading efficiency and retention kinetics of TGFß1 as a model growth factor. At equal concentrations, high MW heparin both loaded and retained the greatest amount of TGFß1, and had the slowest release kinetics, primarily due to the higher affinity with TGFß1 compared to low MW or unfractionated heparin. Subsequently, we tested the effect of TGFß1, presented from various heparin-containing matrices, to differentiate a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs) into endothelial cells and form vascular-like networks in vitro. High MW heparin HyA hydrogels stimulated more robust differentiation of CPCs into endothelial cells, which formed vascular-like networks within the hydrogel. This observation was attributed to the ability of high MW heparin HyA hydrogels to sequester endogenously synthesized angiogenic factors within the matrix. These results demonstrate the importance of molecular weight, fractionation, and concentration of heparin on presentation of heparin-binding growth factors and their effect on stem cell differentiation and lineage specification.


Asunto(s)
Heparina/farmacología , Ácido Hialurónico/farmacología , Hidrogeles/farmacología , Células Madre/efectos de los fármacos , Factor de Crecimiento Transformador beta1/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , Heparina/química , Ácido Hialurónico/química , Hidrogeles/química , Cinética , Ratones , Peso Molecular , Células Madre/citología , Factor de Crecimiento Transformador beta1/química
20.
Heart Fail Rev ; 20(5): 613-9, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26024953

RESUMEN

Injection of various stem cells has been tested with the hopes of improving cardiac function after a myocardial infarction (MI). However, there is continued controversy as to which cell type is best for repair. Due to technical differences in cell isolation, processing, delivery, and cardiac functional assessment by various investigators, it has been difficult to directly compare the results of different cells. Using same techniques to evaluate the efficacy of different cell types, we have separately delivered bone marrow cells (BMCs), cardiospheres (CSs), CS-derived Sca-1(+)/CD45(-) cells, human embryonic stem cell-derived cardiomyocytes, and BMC extract into infarcted murine myocardium and found that all of these treatments reduce infarct size and improve cardiac function post-MI similarly without one regimen being superior to another. The beneficial effects appear to be via paracrine influences. Different progenitors lead to improved cardiac function post-MI, but it is premature to hype any specific cell type at this time.


Asunto(s)
Trasplante de Médula Ósea/métodos , Infarto del Miocardio , Miocitos Cardíacos/fisiología , Trasplante de Células Madre/métodos , Células Madre , Animales , Humanos , Ratones , Infarto del Miocardio/metabolismo , Infarto del Miocardio/terapia , Células Madre/clasificación , Células Madre/metabolismo , Resultado del Tratamiento
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