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2.
Methods Inf Med ; 58(2-03): 71-78, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31514208

RESUMO

OBJECTIVES: The quality of hospital discharge care and patient factors (health and sociodemographic) impact the rates of unplanned readmissions. This study aims to measure the effects of controlling for the patient factors when using readmission rates to quantify the weighted edges between health care providers in a collaboration network. This improved understanding may inform strategies to reduce hospital readmissions, and facilitate quality-improvement initiatives. METHODS: We extracted 4 years of patient, provider, and activity data related to cardiology discharge workflow. A Weibull model was developed to predict the risk of unplanned 30-day readmission. A provider-patient bipartite network was used to connect providers by shared patient encounters. We built collaboration networks and calculated the Shared Positive Outcome Ratio (SPOR) to quantify the relationship between providers by the relative rate of patient outcomes, using both risk-adjusted readmission rates and unadjusted readmission rates. The effect of risk adjustment on the calculation of the SPOR metric was quantified using a permutation test and descriptive statistics. RESULTS: Comparing the collaboration networks consisting of 2,359 provider pairs, we found that SPOR values with risk-adjusted outcomes are significantly different than unadjusted readmission as an outcome measure (p-value = 0.025). The two networks classified the same provider pairs as high-scoring 51.5% of the time, and the same low scoring provider pairs 85.6% of the time. The observed differences in patient demographics and disease characteristics between high-scoring and low-scoring provider pairs were reduced by applying the risk-adjusted model. The risk-adjusted model reduced the average variation across each individual's SPOR scored provider connections. CONCLUSIONS: Risk adjusting unplanned readmission in a collaboration network has an effect on SPOR-weighted edges, especially on classifying high-scoring SPOR provider pairs. The risk-adjusted model reduces the variance of providers' connections and balances shared patient characteristics between low- and high-scoring provider pairs. This indicates that the risk-adjusted SPOR edges better measure the impact of collaboration on readmissions by accounting for patients' risk of readmission.

3.
Circulation ; 140(18): 1463-1476, 2019 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-31524498

RESUMO

BACKGROUND: Outcome trials in patients with type 2 diabetes mellitus have demonstrated reduced hospitalizations for heart failure (HF) with sodium-glucose co-transporter-2 inhibitors. However, few of these patients had HF, and those that did were not well-characterized. Thus, the effects of sodium-glucose co-transporter-2 inhibitors in patients with established HF with reduced ejection fraction, including those with and without type 2 diabetes mellitus, remain unknown. METHODS: DEFINE-HF (Dapagliflozin Effects on Biomarkers, Symptoms and Functional Status in Patients with HF with Reduced Ejection Fraction) was an investigator-initiated, multi-center, randomized controlled trial of HF patients with left ventricular ejection fraction ≤40%, New York Heart Association (NYHA) class II-III, estimated glomerular filtration rate ≥30 mL/min/1.73m2, and elevated natriuretic peptides. In total, 263 patients were randomized to dapagliflozin 10 mg daily or placebo for 12 weeks. Dual primary outcomes were (1) mean NT-proBNP (N-terminal pro b-type natriuretic peptide) and (2) proportion of patients with ≥5-point increase in HF disease-specific health status on the Kansas City Cardiomyopathy Questionnaire overall summary score, or a ≥20% decrease in NT-proBNP. RESULTS: Patient characteristics reflected stable, chronic HF with reduced ejection fraction with high use of optimal medical therapy. There was no significant difference in average 6- and 12-week adjusted NT-proBNP with dapagliflozin versus placebo (1133 pg/dL (95% CI 1036-1238) vs 1191 pg/dL (95% CI 1089-1304), P=0.43). For the second dual-primary outcome of a meaningful improvement in Kansas City Cardiomyopathy Questionnaire overall summary score or NT-proBNP, 61.5% of dapagliflozin-treated patients met this end point versus 50.4% with placebo (adjusted OR 1.8, 95% CI 1.03-3.06, nominal P=0.039). This was attributable to both higher proportions of patients with ≥5-point improvement in Kansas City Cardiomyopathy Questionnaire overall summary score (42.9 vs 32.5%, adjusted OR 1.73, 95% CI 0.98-3.05), and ≥20% reduction in NT-proBNP (44.0 vs 29.4%, adjusted OR 1.9, 95% CI 1.1-3.3) by 12 weeks. Results were consistent among patients with or without type 2 diabetes mellitus, and other prespecified subgroups (all P values for interaction=NS). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, use of dapagliflozin over 12 weeks did not affect mean NT-proBNP but increased the proportion of patients experiencing clinically meaningful improvements in HF-related health status or natriuretic peptides. Benefits of dapagliflozin on clinically meaningful HF measures appear to extend to patients without type 2 diabetes mellitus. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02653482.

5.
J Proteome Res ; 17(6): 2156-2164, 2018 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-29649363

RESUMO

Top-down proteomics (TDP) allows precise determination/characterization of the different proteoforms derived from the expression of a single gene. In this study, we targeted apolipoprotein A-I (ApoA-I), a mediator of high-density-lipoprotein cholesterol efflux (HDL-E), which is inversely associated with coronary heart disease risk. Absolute ApoA-I concentration and allelic variation only partially explain interindividual HDL-E variation. Therefore, we hypothesize that differences in HDL-E are associated with the abundances of different ApoA-I proteoforms. Here, we present a targeted TDP methodology to characterize ApoA-I proteoforms in serum samples and compare their abundances between individuals. We characterized 18 ApoA-I proteoforms using selected-ion monitoring coupled to electron-transfer dissociation mass spectrometry. We then compared the abundances of these proteoforms between two groups of four participants, representing the individuals with highest and lowest HDL-E values within the Chicago Healthy Aging Study ( n = 420). Six proteoforms showed significantly ( p < 0.0005) higher intensity in high HDL-E individuals: canonical ApoA-I [fold difference (fd) = 1.17], carboxymethylated ApoA-I (fd = 1.24) and, with highest difference, four fatty acylated forms: palmitoylated (fd = 2.16), oleoylated (fd = 2.08), arachidonoylated (fd = 2.31) and one bearing two modifications: palmitoylation and truncation (fd = 2.13). These results demonstrate translational potential for targeted TDP in revealing, with high sensitivity, associations between interindividual proteoform variation and physiological differences underlying disease risk.


Assuntos
Apolipoproteína A-I/sangue , Lipoproteínas HDL/metabolismo , Proteômica/métodos , Idoso , Transporte Biológico , Colesterol/metabolismo , Feminino , Humanos , Masculino , Espectrometria de Massas/métodos , Medicina de Precisão , Processamento de Proteína Pós-Traducional , Manejo de Espécimes
6.
JAMA Cardiol ; 3(1): 69-74, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-29214319

RESUMO

Importance: While it is known that long-term intensive athletic training is associated with cardiac structural changes that can be reflected on surface electrocardiograms (ECGs), there is a paucity of sport-specific ECG data. This study seeks to clarify the applicability of existing athlete ECG interpretation criteria to elite basketball players, an athlete group shown to develop significant athletic cardiac remodeling. Objective: To generate normative ECG data for National Basketball Association (NBA) athletes and to assess the accuracy of athlete ECG interpretation criteria in this population. Design, Setting, and Participants: The NBA has partnered with Columbia University Medical Center to annually perform a review of policy-mandated annual preseason ECGs and stress echocardiograms for all players and predraft participants. This observational study includes the preseason ECG examinations of NBA athletes who participated in the 2013-2014 and 2014-2015 seasons, plus all participants in the 2014 and 2015 NBA predraft combines. Examinations were performed from July 2013 to May 2015. Data analysis was performed between December 2015 and March 2017. Exposures: Active roster or draft status in the NBA and routine preseason ECGs and echocardiograms. Main Outcomes and Measures: Baseline quantitative ECG variables were measured and ECG data qualitatively analyzed using 3 existing, athlete-specific interpretation criteria: Seattle (2012), refined (2014), and international (2017). Abnormal ECG findings were compared with matched echocardiographic data. Results: Of 519 male athletes, 409 (78.8%) were African American, 96 (18.5%) were white, and the remaining 14 (2.7%) were of other races/ethnicities; 115 were predraft combine participants, and the remaining 404 were on active rosters of NBA teams. The mean (SD) age was 24.8 (4.3) years. Physiologic, training-related changes were present in 462 (89.0%) athletes in the study. Under Seattle criteria, 131 (25.2%) had abnormal findings, compared with 108 (20.8%) and 81 (15.6%) under refined and international criteria, respectively. Increased age and increased left ventricular relative wall thickness (RWT) on echocardiogram were highly associated with abnormal ECG classifications; 17 of 186 athletes (9.1%) in the youngest age group (age 18-22 years) had abnormal ECGs compared with 36 of the 159 athletes (22.6%) in the oldest age group (age 27-39 years) (odds ratio, 2.9; 95% CI, 1.6-5.4; P < .001). Abnormal T-wave inversions (TWI) were present in 32 athletes (6.2%), and this was associated with smaller left ventricular cavity size and increased RWT. One of the 172 athletes (0.6%) in the lowest RWT group (range, 0.24-0.35) had TWIs compared with 24 of the 163 athletes (14.7%) in the highest RWT group (range, 0.41-0.57) (odds ratio, 29.5; 95% CI, 3.9-221.0; P < .001). Conclusions and Relevance: Despite the improved specificity of the international recommendations over previous athlete-specific ECG criteria, abnormal ECG classification rates remain high in NBA athletes. The development of left ventricular concentric remodeling appears to have a significant influence on the prevalence of abnormal ECG classification and repolarization abnormalities in this athlete group.


Assuntos
Basquetebol/fisiologia , Adulto , Arritmias Cardíacas/diagnóstico , Arritmias Cardíacas/fisiopatologia , Atletas/estatística & dados numéricos , Ecocardiografia , Eletrocardiografia , Humanos , Masculino , Estados Unidos , Remodelação Ventricular/fisiologia
8.
Artigo em Inglês | MEDLINE | ID: mdl-28303243

RESUMO

OBJECTIVE: To quantify the association between high-density lipoprotein (HDL) subfractions, efflux capacity, and inflammatory markers at baseline and the effect of supervised exercise on these HDL parameters in patients with peripheral artery disease (PAD). METHODS: The study to improve leg circulation (SILC) was a randomized trial of supervised treadmill exercise, leg resistance training, or control in individuals with PAD. In a post hoc cross-sectional analysis, we quantified the associations between baseline HDL subfraction concentrations (HDL2 and HDL3), HDL-C efflux capacity, and inflammatory markers [C-reactive protein (CRP) and interleukin-6 (IL-6)]. We then examined the effect of supervised exercise on changes in these lipoprotein parameters and inflammatory markers in 88 patients from SILC. RESULTS: Baseline HDL-C efflux capacity was associated with baseline concentrations of HDL2 (ß = 0.008, p = 0.0106), HDL3 (ß = 0.013, p < 0.0001), and IL-6 (ß = -0.019, p = 0.03). Baseline HDL3 concentration was inversely associated with IL-6 concentration (ß = -0.99, p = 0.008). Compared to control, changes in HDL2, HDL3, normalized HDL-C efflux capacity, CRP, or IL-6 were not significantly different at 6 months following the structured exercise intervention. CONCLUSION: HDL efflux and HDL3 were inversely associated with IL-6 in PAD patients. Structured exercise was not associated with changes in HDL subfractions, HDL-C efflux capacity, CRP, and IL-6 in PAD patients. Our preliminary findings support the theory that inflammation may adversely affect HDL structure and function; however, further studies are needed to evaluate these findings.

9.
J Lipid Res ; 58(3): 600-606, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28049656

RESUMO

HDL efflux capacity and HDL particle size are associated with atherosclerotic CVD (ASCVD) events in middle-aged individuals; however, it is unclear whether these associations are present in older adults. We sampled 402 Chicago Healthy Aging Study participants who underwent a dedicated carotid MRI assessment for lipid-rich necrotic core (LRNC) plaque. We measured HDL particle size, HDL particle number, and LDL particle number with NMR spectroscopy, as well as HDL efflux capacity. We quantified the associations between HDL particle size and HDL efflux using adjusted linear regression models. We quantified associations between the presence of LRNC and HDL and LDL particle number, HDL particle size, and HDL efflux capacity using adjusted logistic regression models. HDL efflux capacity was directly associated with large (ß = 0.037, P < 0.001) and medium (ß = 0.0065, P = 0.002) HDL particle concentration and inversely associated with small (ß = -0.0049, P = 0.018) HDL particle concentration in multivariable adjusted models. HDL efflux capacity and HDL particle number were inversely associated with prevalent LRNC plaque in unadjusted models (odds ratio: 0.5; 95% confidence interval: 0.26, 0.96), but not after multivariable adjustment. HDL particle size was not associated with prevalent LRNC. HDL particle size was significantly associated with HDL efflux capacity, suggesting that differences in HDL efflux capacity may be due to structural differences in HDL particles. Future research is needed to determine whether HDL efflux is a marker of ASCVD risk in older populations.


Assuntos
Envelhecimento/sangue , Doenças das Artérias Carótidas/sangue , HDL-Colesterol/sangue , Lipoproteínas HDL/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento/patologia , Biomarcadores/sangue , Doenças das Artérias Carótidas/patologia , Chicago , LDL-Colesterol/sangue , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Fatores de Risco
10.
J Am Med Inform Assoc ; 24(2): 288-294, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27589944

RESUMO

Objective: Using Failure Mode and Effects Analysis (FMEA) as an example quality improvement approach, our objective was to evaluate whether secondary use of orders, forms, and notes recorded by the electronic health record (EHR) during daily practice can enhance the accuracy of process maps used to guide improvement. We examined discrepancies between expected and observed activities and individuals involved in a high-risk process and devised diagnostic measures for understanding discrepancies that may be used to inform quality improvement planning. Methods: Inpatient cardiology unit staff developed a process map of discharge from the unit. We matched activities and providers identified on the process map to EHR data. Using four diagnostic measures, we analyzed discrepancies between expectation and observation. Results: EHR data showed that 35% of activities were completed by unexpected providers, including providers from 12 categories not identified as part of the discharge workflow. The EHR also revealed sub-components of process activities not identified on the process map. Additional information from the EHR was used to revise the process map and show differences between expectation and observation. Conclusion: Findings suggest EHR data may reveal gaps in process maps used for quality improvement and identify characteristics about workflow activities that can identify perspectives for inclusion in an FMEA. Organizations with access to EHR data may be able to leverage clinical documentation to enhance process maps used for quality improvement. While focused on FMEA protocols, findings from this study may be applicable to other quality activities that require process maps.


Assuntos
Serviço Hospitalar de Cardiologia/organização & administração , Registros Eletrônicos de Saúde , Análise do Modo e do Efeito de Falhas na Assistência à Saúde , Melhoria de Qualidade , Documentação/métodos , Humanos , Alta do Paciente
11.
J Mater Chem B ; 4(2): 188-197, 2016 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-27069624

RESUMO

High-density lipoproteins (HDL) are a class of natural nanostructures found in the blood and are composed of lipids, proteins, and nucleic acids (e.g. microRNA). Their size, which appears to be well-suited for both tissue penetration/retention as well as payload delivery, long circulation half-life, avoidance of endosomal sequestration, and potential low toxicity are all excellent properties to model in a drug delivery vehicle. In this review, we consider high-density lipoproteins for therapeutic delivery systems. First we discuss the structure and function of natural HDL, describing in detail its biogenesis and transformation from immature, discoidal forms, to more mature, spherical forms. Next we consider features of HDL making them suitable vehicles for drug delivery. We then describe the use of natural HDL, discoidal HDL analogs, and spherical HDL analogs to deliver various classes of drugs, including small molecules, lipids, and oligonucleotides. We briefly consider the notion that the drug delivery vehicles themselves are therapeutic, constituting entities that exhibit "theralivery." Finally, we discuss challenges and future directions in the field.

12.
Circ Cardiovasc Qual Outcomes ; 9(6): 670-678, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-28051772

RESUMO

BACKGROUND: The nature of teamwork in healthcare is complex and interdisciplinary, and provider collaboration based on shared patient encounters is crucial to its success. Characterizing the intensity of working relationships with risk-adjusted patient outcomes supplies insight into provider interactions in a hospital environment. METHODS AND RESULTS: We extracted 4 years of patient, provider, and activity data for encounters in an inpatient cardiology unit from Northwestern Medicine's Enterprise Data Warehouse. We then created a provider-patient network to identify healthcare providers who jointly participated in patient encounters and calculated satisfaction rates for provider-provider pairs. We demonstrated the application of a novel parameter, the shared positive outcome ratio, a measure that assesses the strength of a patient-sharing relationship between 2 providers based on risk-adjusted encounter outcomes. We compared an observed collaboration network of 334 providers and 3453 relationships to 1000 networks with shared positive outcome ratio scores based on randomized outcomes and found 188 collaborative relationships between pairs of providers that showed significantly higher than expected patient satisfaction ratings. A group of 22 providers performed exceptionally in terms of patient satisfaction. Our results indicate high variability in collaboration scores across the network and highlight our ability to identify relationships with both higher and lower than expected scores across a set of shared patient encounters. CONCLUSIONS: Satisfaction rates seem to vary across different teams of providers. Team collaboration can be quantified using a composite measure of collaboration across provider pairs. Tracking provider pair outcomes over a sufficient set of shared encounters may inform quality improvement strategies such as optimizing team staffing, identifying characteristics and practices of high-performing teams, developing evidence-based team guidelines, and redesigning inpatient care processes.


Assuntos
Serviço Hospitalar de Cardiologia/organização & administração , Doenças Cardiovasculares/terapia , Prestação Integrada de Cuidados de Saúde/organização & administração , Corpo Clínico Hospitalar/organização & administração , Recursos Humanos de Enfermagem no Hospital/organização & administração , Equipe de Assistência ao Paciente/organização & administração , /organização & administração , Doenças Cardiovasculares/diagnóstico , Comportamento Cooperativo , Mineração de Dados/métodos , Bases de Dados Factuais , Humanos , Pacientes Internados , Comunicação Interdisciplinar , Modelos Logísticos , Satisfação do Paciente , Melhoria de Qualidade/normas , Indicadores de Qualidade em Assistência à Saúde/organização & administração , Estudos Retrospectivos , Fatores de Risco , Resultado do Tratamento
13.
Sci Rep ; 5: 15724, 2015 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-26511855

RESUMO

Exosomes are nanoscale vesicles that mediate intercellular communication. Cellular exosome uptake mechanisms are not well defined partly due to the lack of specific inhibitors of this complex cellular process. Exosome uptake depends on cholesterol-rich membrane microdomains called lipid rafts, and can be blocked by non-specific depletion of plasma membrane cholesterol. Scavenger receptor type B-1 (SR-B1), found in lipid rafts, is a receptor for cholesterol-rich high-density lipoproteins (HDL). We hypothesized that a synthetic nanoparticle mimic of HDL (HDL NP) that binds SR-B1 and removes cholesterol through this receptor would inhibit cellular exosome uptake. In cell models, our data show that HDL NPs bind SR-B1, activate cholesterol efflux, and attenuate the influx of esterified cholesterol. As a result, HDL NP treatment results in decreased dynamics and clustering of SR-B1 contained in lipid rafts and potently inhibits cellular exosome uptake. Thus, SR-B1 and targeted HDL NPs provide a fundamental advance in studying cholesterol-dependent cellular uptake mechanisms.


Assuntos
Materiais Biomiméticos , Colesterol/metabolismo , Exossomos/metabolismo , Lipoproteínas HDL , Nanopartículas/química , Receptores Depuradores Classe B/metabolismo , Animais , Transporte Biológico Ativo , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linhagem Celular Tumoral , Humanos , Lipoproteínas HDL/química , Lipoproteínas HDL/farmacologia , Camundongos
14.
EuPA Open Proteom ; 8: 40-47, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-26753126

RESUMO

Enabling the implementation of top down proteomic techniques within clinical workflows requires a dramatic increase in sensitivity. It has been previously demonstrated that electrospray ionization (ESI) becomes more efficient with decreasing volumetric flow rates at the emitter. Therefore, narrow inner diameter (I.D.) columns used in front-end chromatographic separations yield increased sensitivity. However, the smaller cross-sectional area of a narrow I.D. column places a larger fraction of the eluent in fluid communication with the electrode within the high voltage union that facilitates electrospray ionization (ESI), leading to increased oxidation of solution-phase proteins. Oxidation of proteins alters their chemical state of the protein, complicates data analysis, and reduces the depth of proteome coverage attained in a typical top-down proteomics experiment. Excessive protein oxidation results in poor deconvolution and exact mass calculations from MS1 spectra, interferes with peak isolation for MS/MS fragmentation, and effectively reduces sensitivity by splitting ion current. All of these factors deteriorate top down mass spectral data quality, an effect that becomes more pronounced as column diameter decreases. Artificial protein oxidation can also mislead investigations of in vivo protein oxidation. All of these effects are accentuated in comparison to bottom up proteomics due to the increased probability of having oxidizable residues within a particular species with increasing mass. Herein, we describe a configuration (which we term "Low Protein Oxidation (LPOx)") for proteomics experiments created by re-arranging liquid chromatography (LC) plumbing and present its application to artificial protein oxidation and show a marked improvement in detection sensitivity. Using a standard mixture of five intact proteins, we demonstrate that the LPOx configuration reduces protein oxidation up to 90% using 50 µm I.D. columns when compared to a conventional LC plumbing configuration with 50 µm I.D. column. As a proof-of-concept study, at least 11 distinct proteoforms of serum Apolipoprotein A1 were detected with the LPOx configuration. This innovative LC configuration can be applied to the top down identification and characterization of proteoforms obscured by abundant artificial protein oxidation at low flowrates, all while using reduced amounts of valuable protein samples.

15.
J Clin Invest ; 124(2): 617-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24382354

RESUMO

Doxorubicin is an effective anticancer drug with known cardiotoxic side effects. It has been hypothesized that doxorubicin-dependent cardiotoxicity occurs through ROS production and possibly cellular iron accumulation. Here, we found that cardiotoxicity develops through the preferential accumulation of iron inside the mitochondria following doxorubicin treatment. In isolated cardiomyocytes, doxorubicin became concentrated in the mitochondria and increased both mitochondrial iron and cellular ROS levels. Overexpression of ABCB8, a mitochondrial protein that facilitates iron export, in vitro and in the hearts of transgenic mice decreased mitochondrial iron and cellular ROS and protected against doxorubicin-induced cardiomyopathy. Dexrazoxane, a drug that attenuates doxorubicin-induced cardiotoxicity, decreased mitochondrial iron levels and reversed doxorubicin-induced cardiac damage. Finally, hearts from patients with doxorubicin-induced cardiomyopathy had markedly higher mitochondrial iron levels than hearts from patients with other types of cardiomyopathies or normal cardiac function. These results suggest that the cardiotoxic effects of doxorubicin develop from mitochondrial iron accumulation and that reducing mitochondrial iron levels protects against doxorubicin-induced cardiomyopathy.


Assuntos
Antineoplásicos/efeitos adversos , Doxorrubicina/efeitos adversos , Coração/efeitos dos fármacos , Ferro/metabolismo , Mitocôndrias/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Cardiotônicos/química , Cruzamentos Genéticos , DNA Topoisomerases Tipo II/metabolismo , Proteínas de Ligação a DNA/metabolismo , Desferroxamina/química , Dexrazoxano/química , Relação Dose-Resposta a Droga , Ecocardiografia , Hemodinâmica , Humanos , Peroxidação de Lipídeos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Miócitos Cardíacos/efeitos dos fármacos , RNA Interferente Pequeno/metabolismo , Espécies Reativas de Oxigênio , Inibidores da Topoisomerase II/química
16.
Adv Drug Deliv Rev ; 65(5): 649-62, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-22921597

RESUMO

High density lipoproteins (HDLs) are dynamic natural nanoparticles best known for their role in cholesterol transport and the inverse correlation that exists between blood HDL levels and the risk of developing coronary heart disease. In addition, enhanced HDL-cholesterol uptake has been demonstrated in several human cancers. As such, the use of HDL as a therapeutic and as a vehicle for systemic delivery of drugs and as imaging agents is increasingly important. HDLs exist on a continuum from the secreted HDL-scaffolding protein, apolipoprotein A-1 (Apo A1), to complex, spherical "mature" HDLs. Aspects of HDL particles including their size, shape, and surface chemical composition are being recognized as critical to their diverse biological functions. Here we review HDL biology; strategies for synthesizing HDLs; data supporting the clinical use and benefit of directly administered HDL; a rationale for developing synthetic methods for spherical, mature HDLs; and, the potential to employ HDLs as therapies, imaging agents, and drug delivery vehicles. Importantly, methods that utilize nanoparticle templates to control synthetic HDL size, shape, and surface chemistry are highlighted.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Lipoproteínas HDL/síntese química , Terapia de Alvo Molecular/métodos , Nanopartículas/química , Animais , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/genética , Humanos , Lipoproteínas HDL/administração & dosagem , Nanopartículas/administração & dosagem
17.
Proc Natl Acad Sci U S A ; 109(11): 4152-7, 2012 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-22375032

RESUMO

Mitochondrial iron levels are tightly regulated, as iron is essential for the synthesis of Fe/S clusters and heme in the mitochondria, but high levels can cause oxidative stress. The ATP-binding cassette (ABC) transporter ABCB8 is a mitochondrial inner membrane protein with an unknown function. Here, we show that ABCB8 is involved in mitochondrial iron export and is essential for baseline cardiac function. Induced genetic deletion of ABCB8 in mouse hearts resulted in mitochondrial iron accumulation and cardiomyopathy, as assessed by echocardiography and invasive hemodynamics. Mice with ABCB8 deletion in the heart also displayed mitochondrial damage, and higher levels of reactive oxygen species and cell death. Down-regulation of ABCB8 in vitro resulted in decreased iron export from isolated mitochondria, whereas its overexpression had the opposite effect. Furthermore, ABCB8 is needed for the maturation of the cytosolic Fe/S proteins, as its deletion in vitro and in vivo led to decreased activity of cytosolic, but not mitochondrial, iron-sulfur-containing enzymes. These results indicate that ABCB8 is essential for normal cardiac function, maintenance of mitochondrial iron homeostasis and maturation of cytosolic Fe/S proteins. In summary, this report provides characterization of a protein involved in mitochondrial iron export.


Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Cardiomiopatias/metabolismo , Cardiomiopatias/patologia , Deleção de Genes , Ferro/metabolismo , Mitocôndrias/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico , Cardiomiopatias/complicações , Cardiomiopatias/fisiopatologia , Citosol/metabolismo , Regulação para Baixo/genética , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/patologia , Cardiopatias Congênitas/fisiopatologia , Testes de Função Cardíaca , Proteínas com Ferro-Enxofre/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Ratos
18.
Am J Physiol Heart Circ Physiol ; 301(4): H1519-30, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21841015

RESUMO

microRNA-210 (miR-210) is upregulated in hypoxia, but its function in cardiomyocytes and its regulation in response to hypoxia are not well characterized. The purpose of this study was to identify upstream regulators of miR-210, as well as to characterize miR-210's function in cardiomyocytes. We first showed miR-210 is upregulated through both hypoxia-inducible factor (HIF)-dependent and -independent pathways, since aryl hydrocarbon nuclear translocator (ARNT) knockout mouse embryonic fibroblasts (MEF), lacking intact HIF signaling, still displayed increased miR-210 levels in hypoxia. To determine the mechanism for HIF-independent regulation of miR-210, we focused on p53 and protein kinase B (Akt). Overexpression of p53 in wild-type MEFs induced miR-210, whereas p53 overexpression in ARNT knockout MEFs did not, suggesting p53 regulates miR-210 in a HIF-dependent mechanism. Akt inhibition reduced miR-210 induction by hypoxia, whereas Akt overexpression increased miR-210 levels in both wild-type and ARNT knockout MEFs, indicating Akt regulation of miR-210 is HIF-independent. We then studied the effects of miR-210 in cardiomyocytes. Overexpression of miR-210 reduced cell death in response to oxidative stress and reduced reactive oxygen species (ROS) production both at baseline and after treatment with antimycin A. Furthermore, downregulation of miR-210 increased ROS after hypoxia-reoxygenation. To determine a mechanism for the cytoprotective effects of miR-210, we focused on the predicted target, apoptosis-inducing factor, mitochondrion-associated 3 (AIFM3), known to induce cell death. Although miR-210 reduced AIFM3 levels, overexpression of AIFM3 in the presence of miR-210 overexpression did not reduce cellular viability either at baseline or after hydrogen peroxide treatment, suggesting AIFM3 does not mediate miR-210's cytoprotective effects. Furthermore, HIF-3α, a negative regulator of HIF signaling, is targeted by miR-210, but miR-210 does not modulate HIF activity. In conclusion, we demonstrate a novel role for p53 and Akt in regulating miR-210 and demonstrate that, in cardiomyocytes, miR-210 exerts cytoprotective effects, potentially by reducing mitochondrial ROS production.


Assuntos
Cardiotônicos , MicroRNAs/biossíntese , Miócitos Cardíacos/metabolismo , Proteína Oncogênica v-akt/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Adenoviridae/genética , Animais , Western Blotting , Morte Celular/fisiologia , Hipóxia Celular/fisiologia , Células Cultivadas , Citometria de Fluxo , Células HEK293 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Luciferases/metabolismo , Potenciais da Membrana/fisiologia , Camundongos , MicroRNAs/genética , Mitocôndrias Cardíacas/fisiologia , Plasmídeos/genética , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Transfecção , Regulação para Cima/fisiologia
19.
Nano Lett ; 11(3): 1208-14, 2011 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-21319839

RESUMO

We report a gold nanoparticle-templated high density lipoprotein (HDL AuNP) platform for gene therapy that combines lipid-based nucleic acid transfection strategies with HDL biomimicry. For proof-of-concept, HDL AuNPs are shown to adsorb antisense cholesterylated DNA. The conjugates are internalized by human cells, can be tracked within cells using transmission electron microscopy, and regulate target gene expression. Overall, the ability to directly image the AuNP core within cells, the chemical tailorability of the HDL AuNP platform, and the potential for cell-specific targeting afforded by HDL biomimicry make this platform appealing for nucleic acid delivery.


Assuntos
Lipoproteínas HDL/química , Mimetismo Molecular , Nanopartículas , Ácidos Nucleicos/administração & dosagem , Linhagem Celular , Humanos , Microscopia Confocal , Microscopia Eletrônica de Transmissão , Microscopia de Fluorescência
20.
Trends Mol Med ; 16(12): 553-60, 2010 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21087901

RESUMO

Atherosclerosis is the disease mechanism responsible for coronary heart disease (CHD), the leading cause of death worldwide. One strategy to combat atherosclerosis is to increase the amount of circulating high-density lipoproteins (HDL), which transport cholesterol from peripheral tissues to the liver for excretion. The process, known as reverse cholesterol transport, is thought to be one of the main reasons for the significant inverse correlation observed between HDL blood levels and the development of CHD. This article highlights the most common strategies for treating atherosclerosis using HDL. We further detail potential treatment opportunities that utilize nanotechnology to increase the amount of HDL in circulation. The synthesis of biomimetic HDL nanostructures that replicate the chemical and physical properties of natural HDL provides novel materials for investigating the structure-function relationships of HDL and for potential new therapeutics to combat CHD.


Assuntos
Lipoproteínas HDL/síntese química , Nanotecnologia , Animais , Doença das Coronárias/sangue , Doença das Coronárias/tratamento farmacológico , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas HDL/uso terapêutico , Nanopartículas Metálicas/química
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