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1.
bioRxiv ; 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34642693

RESUMO

The COVID-19 pandemic remains a global health crisis, yet, the immunopathological mechanisms driving the development of severe disease remain poorly defined. Here, we utilize a rhesus macaque (RM) model of SARS-CoV-2 infection to delineate perturbations in the innate immune system during acute infection using an integrated systems analysis. We found that SARS-CoV-2 initiated a rapid infiltration (two days post infection) of plasmacytoid dendritic cells into the lower airway, commensurate with IFNA production, natural killer cell activation, and induction of interferon-stimulated genes. At this early interval, we also observed a significant increase of blood CD14-CD16+ monocytes. To dissect the contribution of lung myeloid subsets to airway inflammation, we generated a novel compendium of RM-specific lung macrophage gene expression using a combination of sc-RNA-Seq data and bulk RNA-Seq of purified populations under steady state conditions. Using these tools, we generated a longitudinal sc-RNA-seq dataset of airway cells in SARS-CoV-2-infected RMs. We identified that SARS-CoV-2 infection elicited a rapid recruitment of two subsets of macrophages into the airway: a C206+MRC1-population resembling murine interstitial macrophages, and a TREM2+ population consistent with CCR2+ infiltrating monocytes, into the alveolar space. These subsets were the predominant source of inflammatory cytokines, accounting for ~75% of IL6 and TNF production, and >90% of IL10 production, whereas the contribution of CD206+MRC+ alveolar macrophages was significantly lower. Treatment of SARS-CoV-2 infected RMs with baricitinib (Olumiant ® ), a novel JAK1/2 inhibitor that recently received Emergency Use Authorization for the treatment of hospitalized COVID-19 patients, was remarkably effective in eliminating the influx of infiltrating, non-alveolar macrophages in the alveolar space, with a concomitant reduction of inflammatory cytokines. This study has delineated the major subsets of lung macrophages driving inflammatory and anti-inflammatory cytokine production within the alveolar space during SARS-CoV-2 infection. One sentence summary: Multi-omic analyses of hyperacute SARS-CoV-2 infection in rhesus macaques identified two population of infiltrating macrophages, as the primary orchestrators of inflammation in the lower airway that can be successfully treated with baricitinib.

2.
Nat Biomed Eng ; 5(8): 880-896, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34426676

RESUMO

Fibroblasts can be directly reprogrammed into cardiomyocytes, endothelial cells or smooth muscle cells. Here we report the reprogramming of mouse tail-tip fibroblasts simultaneously into cells resembling these three cell types using the microRNA mimic miR-208b-3p, ascorbic acid and bone morphogenetic protein 4, as well as the formation of tissue-like structures formed by the directly reprogrammed cells. Implantation of the formed cardiovascular tissue into the infarcted hearts of mice led to the migration of reprogrammed cells to the injured tissue, reducing regional cardiac strain and improving cardiac function. The migrated endothelial cells and smooth muscle cells contributed to vessel formation, and the migrated cardiomyocytes, which initially displayed immature characteristics, became mature over time and formed gap junctions with host cardiomyocytes. Direct reprogramming of somatic cells to make cardiac tissue may aid the development of applications in cell therapy, disease modelling and drug discovery for cardiovascular diseases.


Assuntos
Células Endoteliais/transplante , Coração/fisiologia , Infarto do Miocárdio/terapia , Miócitos de Músculo Liso/transplante , Regeneração , Animais , Ácido Ascórbico/farmacologia , Proteína Morfogenética Óssea 4/farmacologia , Reprogramação Celular/efeitos dos fármacos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Fibroblastos/citologia , Fibroblastos/metabolismo , Junções Comunicantes/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Neovascularização Fisiológica , Transcriptoma
3.
Artigo em Inglês | MEDLINE | ID: mdl-34050499

RESUMO

Currently, there is no large animal model of sustained limb ischemia suitable for testing novel angiogenic therapeutics for peripheral artery disease (PAD) such as drugs, genes, materials, or cells. We created a large animal model suitable for efficacy assessment of these therapies by testing 3 swine hind limb ischemia (HLI) variations and quantifying vascular perfusion, muscle histology, and limb function. Ligation of the ipsilateral external and bilateral internal iliac arteries produced sustained gait dysfunction compared to isolated external iliac or unilateral external and internal iliac artery ligations. Hyperemia-dependent muscle perfusion deficits, depressed limb blood pressure, arteriogenesis, muscle atrophy, and microscopic myopathy were quantifiable in ischemic limbs 6 weeks post-ligation. Porcine mesenchymal stromal cells (MSCs) engineered to express a reporter gene were visualized post-administration via positron emission tomography (PET) in vivo. These results establish a preclinical platform enabling better optimization of PAD therapies, including cellular therapeutics, increasing bench-to-bedside translational success. A preclinical platform for porcine studies of peripheral artery disease therapies including (1) a hind limb ischemia model and (2) non-invasive MSC viability and retention assessment via PET.

5.
Cell ; 184(2): 460-475.e21, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33278358

RESUMO

SARS-CoV-2-induced hypercytokinemia and inflammation are critically associated with COVID-19 severity. Baricitinib, a clinically approved JAK1/JAK2 inhibitor, is currently being investigated in COVID-19 clinical trials. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages, and tissues was not reduced with baricitinib. Type I interferon (IFN) antiviral responses and SARS-CoV-2-specific T cell responses remained similar between the two groups. Animals treated with baricitinib showed reduced inflammation, decreased lung infiltration of inflammatory cells, reduced NETosis activity, and more limited lung pathology. Importantly, baricitinib-treated animals had a rapid and remarkably potent suppression of lung macrophage production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for inflammation induced by SARS-CoV-2 infection.


Assuntos
Anti-Inflamatórios/administração & dosagem , Azetidinas/administração & dosagem , COVID-19/tratamento farmacológico , COVID-19/imunologia , Macaca mulatta , Infiltração de Neutrófilos/efeitos dos fármacos , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Sulfonamidas/administração & dosagem , Animais , COVID-19/fisiopatologia , Morte Celular/efeitos dos fármacos , Degranulação Celular/efeitos dos fármacos , Modelos Animais de Doenças , Inflamação/tratamento farmacológico , Inflamação/genética , Inflamação/imunologia , Janus Quinases/antagonistas & inibidores , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/patologia , Ativação Linfocitária/efeitos dos fármacos , Macrófagos Alveolares/imunologia , SARS-CoV-2/fisiologia , Índice de Gravidade de Doença , Linfócitos T/imunologia , Replicação Viral/efeitos dos fármacos
6.
bioRxiv ; 2020 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-32995780

RESUMO

Effective therapeutics aimed at mitigating COVID-19 symptoms are urgently needed. SARS-CoV-2 induced hypercytokinemia and systemic inflammation are associated with disease severity. Baricitinib, a clinically approved JAK1/2 inhibitor with potent anti-inflammatory properties is currently being investigated in COVID-19 human clinical trials. Recent reports suggest that baricitinib may also have antiviral activity in limiting viral endocytosis. Here, we investigated the immunologic and virologic efficacy of baricitinib in a rhesus macaque model of SARS-CoV-2 infection. Viral shedding measured from nasal and throat swabs, bronchoalveolar lavages and tissues was not reduced with baricitinib. Type I IFN antiviral responses and SARS-CoV-2 specific T cell responses remained similar between the two groups. Importantly, however, animals treated with baricitinib showed reduced immune activation, decreased infiltration of neutrophils into the lung, reduced NETosis activity, and more limited lung pathology. Moreover, baricitinib treated animals had a rapid and remarkably potent suppression of alveolar macrophage derived production of cytokines and chemokines responsible for inflammation and neutrophil recruitment. These data support a beneficial role for, and elucidate the immunological mechanisms underlying, the use of baricitinib as a frontline treatment for severe inflammation induced by SARS-CoV-2 infection.

7.
J Leukoc Biol ; 105(6): 1225-1234, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30907983

RESUMO

Neutrophil extracellular traps (NETs) are implicated in autoimmune, thrombotic, malignant, and inflammatory diseases; however, little is known of their endogenous regulation under basal conditions. Inflammatory effects of neutrophils are modulated by extracellular purines such as adenosine (ADO) that is inhibitory or ATP that generally up-regulates effector functions. In order to evaluate the effects of ADO on NETs, human neutrophils were isolated from peripheral venous blood from healthy donors and stimulated to make NETs. Treatment with ADO inhibited NET production as quantified by 2 methods: SYTOX green fluorescence and human neutrophil elastase (HNE)-DNA ELISA assay. Specific ADO receptor agonist and antagonist were tested for their effects on NET production. The ADO 2A receptor (A2A R) agonist CSG21680 inhibited NETs to a similar degree as ADO, whereas the A2A R antagonist ZM241385 prevented ADO's NET-inhibitory effects. Additionally, CD73 is a membrane bound ectonucleotidase expressed on mesenchymal stromal cells (MSCs) that allows manipulation of extracellular purines in tissues such as bone marrow. The effects of MSCs on NET formation were evaluated in coculture. MSCs reduced NET formation in a CD73-dependent manner. These results imply that extracellular purine balance may locally regulate NETosis and may be actively modulated by stromal cells to maintain tissue homeostasis.


Assuntos
Adenosina/imunologia , Armadilhas Extracelulares/imunologia , Neutrófilos/imunologia , 5'-Nucleotidase/imunologia , Técnicas de Cocultura , Proteínas Ligadas por GPI/imunologia , Humanos , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/imunologia , Neutrófilos/citologia , Receptor A2A de Adenosina/imunologia
8.
Circ Arrhythm Electrophysiol ; 11(5): e006408, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29748197

RESUMO

BACKGROUND: Atrial fibrillation (AF) is the most common cardiac arrhythmia. Although treatment options for AF exist, many patients cannot be maintained in normal sinus rhythm. Amiodarone is an effective medication for AF but has limited clinical utility because of off-target tissue toxicity. METHODS: Here, we use a pig model of AF to test the efficacy of an amiodarone-containing polyethylene glycol-based hydrogel. The gel is placed directly on the atrial epicardium through the pericardial space in a minimally invasive procedure using a specially designed catheter. RESULTS: Implantation of amiodarone-containing gel significantly reduced the duration of sustained AF at 21 and 28 days; inducibility of AF was reduced 14 and 21 days post-delivery. Off-target organ drug levels in the liver, lungs, thyroid, and fat were significantly reduced in animals treated with epicardial amiodarone gel compared with systemic controls in small-animal distribution studies. CONCLUSIONS: The pericardium is an underutilized therapeutic site and may be a new treatment strategy for AF and other cardiovascular diseases.


Assuntos
Amiodarona/administração & dosagem , Antiarrítmicos/administração & dosagem , Fibrilação Atrial/prevenção & controle , Portadores de Fármacos , Frequência Cardíaca/efeitos dos fármacos , Pericárdio/efeitos dos fármacos , Polietilenoglicóis/química , Amiodarona/química , Amiodarona/toxicidade , Animais , Antiarrítmicos/química , Antiarrítmicos/toxicidade , Fibrilação Atrial/fisiopatologia , Modelos Animais de Doenças , Composição de Medicamentos , Implantes de Medicamento , Liberação Controlada de Fármacos , Hidrogéis , Masculino , Pericárdio/fisiopatologia , Ratos Sprague-Dawley , Sus scrofa , Fatores de Tempo
9.
J Am Heart Assoc ; 7(2)2018 01 13.
Artigo em Inglês | MEDLINE | ID: mdl-29331956

RESUMO

BACKGROUND: During myocardial ischemia/reperfusion (MI/R) injury, there is extensive release of immunogenic metabolites that activate cells of the innate immune system. These include ATP and AMP, which upregulate chemotaxis, migration, and effector function of early infiltrating inflammatory cells. These cells subsequently drive further tissue devitalization. Mesenchymal stromal cells (MSCs) are a potential treatment modality for MI/R because of their powerful anti-inflammatory capabilities; however, the manner in which they regulate the acute inflammatory milieu requires further elucidation. CD73, an ecto-5'-nucleotidase, may be critical in regulating inflammation by converting pro-inflammatory AMP to anti-inflammatory adenosine. We hypothesized that MSC-mediated conversion of AMP into adenosine reduces inflammation in early MI/R, favoring a micro-environment that attenuates excessive innate immune cell activation and facilitates earlier cardiac recovery. METHODS AND RESULTS: Adult rats were subjected to 30 minutes of MI/R injury. MSCs were encapsulated within a hydrogel vehicle and implanted onto the myocardium. A subset of MSCs were pretreated with the CD73 inhibitor, α,ß-methylene adenosine diphosphate, before implantation. Using liquid chromatography/mass spectrometry, we found that MSCs increase myocardial adenosine availability following injury via CD73 activity. MSCs also reduce innate immune cell infiltration as measured by flow cytometry, and hydrogen peroxide formation as measured by Amplex Red assay. These effects were dependent on MSC-mediated CD73 activity. Finally, through echocardiography we found that CD73 activity on MSCs was critical to optimal protection of cardiac function following MI/R injury. CONCLUSIONS: MSC-mediated conversion of AMP to adenosine by CD73 exerts a powerful anti-inflammatory effect critical for cardiac recovery following MI/R injury.


Assuntos
Adenosina/metabolismo , Imunidade Inata , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Infarto do Miocárdio/cirurgia , Traumatismo por Reperfusão Miocárdica/cirurgia , Miocárdio/metabolismo , Tecidos Suporte , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Difosfato de Adenosina/análogos & derivados , Difosfato de Adenosina/farmacologia , Monofosfato de Adenosina/metabolismo , Animais , Células Cultivadas , Técnicas de Cocultura , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Infarto do Miocárdio/imunologia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/imunologia , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/imunologia , Miocárdio/patologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ratos Sprague-Dawley , Recuperação de Função Fisiológica , Nicho de Células-Tronco
11.
Congenit Heart Dis ; 12(1): 6-16, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27597140

RESUMO

"Frontiers in Fontan Failure" was the title of a 2015 conference sponsored by Children's Healthcare of Atlanta and Emory University School of Medicine. In what is hoped to be the first of many such gatherings, speakers and attendees gathered to discuss the problem of long-term clinical deterioration in these patients. Specific focuses included properly defining the problem and then discussing different treatment strategies, both medical and surgical. The health of the liver after Fontan palliation was a particular point of emphasis, as were quality of life and future directions.


Assuntos
Técnica de Fontan/efeitos adversos , Cardiopatias Congênitas/cirurgia , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Fígado/fisiopatologia , Hepatopatias/etiologia , Hepatopatias/fisiopatologia , Cuidados Paliativos , Qualidade de Vida , Fatores de Risco , Fatores de Tempo , Falha de Tratamento
12.
JACC Basic Transl Sci ; 2(5): 601-609, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30062173

RESUMO

Biomaterials are a new treatment strategy for cardiovascular diseases but are difficult to deliver to the heart in a safe, precise, and translatable way. We developed a method to deliver hydrogels to the epicardium through the pericardial space. Our device creates a temporary compartment for hydrogel delivery and gelation using anatomic structures. The method minimizes risk to patients from embolization, thrombotic occlusion, and arrhythmia. In pigs there were no clinically relevant acute or subacute adverse effects from pericardial hydrogel delivery, making this a translatable strategy to deliver biomaterials to the heart.

13.
J Investig Med High Impact Case Rep ; 4(2): 2324709616646128, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27152317

RESUMO

Diabetic ketoacidosis is a routinely encountered diagnosis in medicine. Physicians are trained early on to look for precipitants. Most clinicians assess for medication compliance, infection, ischemia, and the like. We present a case of pheochromocytoma presenting as "diabetic ketoacidosis." The case serves as an example for broadening the differential diagnosis for patients with similar presentations. Additionally, the case helps inform our understanding of the so-called "stress reactions" that are commonly invoked in clinical rationale.

14.
JACC Basic Transl Sci ; 1(5): 373-375, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30167525
15.
J Tissue Eng Regen Med ; 10(3): 222-32, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23281223

RESUMO

Stem cell-based therapies hold great promise as a clinically viable approach for vascular regeneration. Preclinical studies have been very encouraging and early clinical trials have suggested favourable outcomes. However, significant challenges remain in terms of optimizing cell retention and maintenance of the paracrine effects of implanted cells. To address these issues, we have proposed the use of a cellular encapsulation approach to enhance vascular regeneration. We contained human mesenchymal stem cells (hMSCs) in biocompatible alginate microcapsules for therapeutic treatment in the setting of murine hindlimb ischaemia. This approach supported the paracrine pro-angiogenic activity of hMSCs, prevented incorporation of hMSCs into the host tissue and markedly enhanced their therapeutic effect. While injection of non-encapsulated hMSCs resulted in a 22 ± 10% increase in vascular density and no increase in perfusion, treatment with encapsulated hMSCs resulted in a 70 ± 8% increase in vascular density and 21 ± 7% increase in perfusion. The described cellular encapsulation strategy may help to better define the mechanisms responsible for the beneficial effects of cell-based therapies and provide a therapeutic strategy for inducing vascular growth in the adult. As hMSCs are relatively easy to isolate from patients, and alginate is biocompatible and already used in clinical applications, therapeutic cell encapsulation for vascular repair represents a highly translatable platform for cell-based therapy in humans.


Assuntos
Alginatos/farmacologia , Membro Posterior/irrigação sanguínea , Isquemia/terapia , Células-Tronco Mesenquimais/citologia , Neovascularização Fisiológica/efeitos dos fármacos , Comunicação Parácrina/efeitos dos fármacos , Animais , Cápsulas , Sobrevivência Celular/efeitos dos fármacos , Células Imobilizadas/citologia , Células Imobilizadas/efeitos dos fármacos , Ácido Glucurônico/farmacologia , Ácidos Hexurônicos/farmacologia , Membro Posterior/efeitos dos fármacos , Membro Posterior/patologia , Humanos , Isquemia/patologia , Masculino , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/efeitos dos fármacos , Camundongos Nus , Permeabilidade , Cicatrização/efeitos dos fármacos
17.
J Am Heart Assoc ; 2(5): e000367, 2013 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-24113327

RESUMO

BACKGROUND: Stem cells for cardiac repair have shown promise in preclinical trials, but lower than expected retention, viability, and efficacy. Encapsulation is one potential strategy to increase viable cell retention while facilitating paracrine effects. METHODS AND RESULTS: Human mesenchymal stem cells (hMSC) were encapsulated in alginate and attached to the heart with a hydrogel patch in a rat myocardial infarction (MI) model. Cells were tracked using bioluminescence (BLI) and cardiac function measured by transthoracic echocardiography (TTE) and cardiac magnetic resonance imaging (CMR). Microvasculature was quantified using von Willebrand factor staining and scar measured by Masson's Trichrome. Post-MI ejection fraction by CMR was greatly improved in encapsulated hMSC-treated animals (MI: 34 ± 3%, MI + Gel: 35 ± 3%, MI + Gel + hMSC: 39 ± 2%, MI + Gel + encapsulated hMSC: 56 ± 1%; n = 4 per group; P < 0.01). Data represent mean ± SEM. By TTE, encapsulated hMSC-treated animals had improved fractional shortening. Longitudinal BLI showed greatest hMSC retention when the cells were encapsulated (P < 0.05). Scar size at 28 days was significantly reduced in encapsulated hMSC-treated animals (MI: 12 ± 1%, n = 8; MI + Gel: 14 ± 2%, n = 7; MI + Gel + hMSC: 14 ± 1%, n = 7; MI+Gel+encapsulated hMSC: 7 ± 1%, n = 6; P < 0.05). There was a large increase in microvascular density in the peri-infarct area (MI: 121 ± 10, n = 7; MI + Gel: 153 ± 26, n = 5; MI + Gel + hMSC: 198 ± 18, n = 7; MI + Gel + encapsulated hMSC: 828 ± 56 vessels/mm2, n = 6; P < 0.01). CONCLUSIONS: Alginate encapsulation improved retention of hMSCs and facilitated paracrine effects such as increased peri-infarct microvasculature and decreased scar. Encapsulation of MSCs improved cardiac function post-MI and represents a new, translatable strategy for optimization of regenerative therapies for cardiovascular diseases.


Assuntos
Transplante de Células-Tronco Mesenquimais/métodos , Infarto do Miocárdio/cirurgia , Animais , Técnicas de Cultura de Células/métodos , Sobrevivência de Enxerto , Humanos , Masculino , Ratos
18.
Circulation ; 124(11 Suppl): S18-26, 2011 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-21911811

RESUMO

BACKGROUND: Experimentally, exogenous administration of recombinant stromal cell-derived factor-1α (SDF) enhances neovasculogenesis and cardiac function after myocardial infarction. Smaller analogs of SDF may provide translational advantages including enhanced stability and function, ease of synthesis, lower cost, and potential modulated delivery via engineered biomaterials. In this study, computational protein design was used to create a more efficient evolution of the native SDF protein. METHODS AND RESULTS: Protein structure modeling was used to engineer an SDF polypeptide analog (engineered SDF analog [ESA]) that splices the N-terminus (activation and binding) and C-terminus (extracellular stabilization) with a diproline segment designed to limit the conformational flexibility of the peptide backbone and retain the relative orientation of these segments observed in the native structure of SDF. Endothelial progenitor cells (EPCs) in ESA gradient, assayed by Boyden chamber, showed significantly increased migration compared with both SDF and control gradients. EPC receptor activation was evaluated by quantification of phosphorylated AKT, and cells treated with ESA yielded significantly greater phosphorylated AKT levels than SDF and control cells. Angiogenic growth factor assays revealed a distinct increase in angiopoietin-1 expression in the ESA- and SDF-treated hearts. In addition, CD-1 mice (n=30) underwent ligation of the left anterior descending coronary artery and peri-infarct intramyocardial injection of ESA, SDF-1α, or saline. At 2 weeks, echocardiography demonstrated a significant gain in ejection fraction, cardiac output, stroke volume, and fractional area change in mice treated with ESA compared with controls. CONCLUSIONS: Compared with native SDF, a novel engineered SDF polypeptide analog (ESA) more efficiently induces EPC migration and improves post-myocardial infarction cardiac function and thus offers a more clinically translatable neovasculogenic therapy.


Assuntos
Proteínas Angiogênicas/química , Proteínas Angiogênicas/farmacologia , Quimiocina CXCL12/química , Quimiocina CXCL12/farmacologia , Biologia Computacional/métodos , Neovascularização Fisiológica/efeitos dos fármacos , Engenharia de Proteínas/métodos , Proteínas Angiogênicas/uso terapêutico , Animais , Débito Cardíaco/efeitos dos fármacos , Débito Cardíaco/fisiologia , Movimento Celular/efeitos dos fármacos , Movimento Celular/fisiologia , Células Cultivadas , Quimiocina CXCL12/uso terapêutico , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiologia , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos , Modelos Animais , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/prevenção & controle , Neovascularização Fisiológica/fisiologia , Ratos , Ratos Wistar , Células-Tronco/citologia , Células-Tronco/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Volume Sistólico/fisiologia
19.
J Cardiovasc Transl Res ; 4(5): 644-5, 2011 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-21850557

RESUMO

Targeting drugs and nanoparticles to cardiomyocytes has been an elusive challenge. Cardiomyocytes are inherently non-phagocytic and their environment is subjected to contractile forces which tend to expel injected and catheter-delivered drugs. In this issue, a novel-targeting strategy, N-acetyl-glucosamine (GlcNAc) coating, is shown to enhance cardiomyocyte nanoparticle uptake both in vitro and in vivo. Many effective and proven therapies for myocardial infarction are in clinical use thus raising the bar for the translation of new technologies. Nevertheless, GlcNAc targeting represents a promising approach for improved targeting of drug therapies to cardiomyocytes.


Assuntos
Acetilglucosamina/química , Fármacos Cardiovasculares/administração & dosagem , Portadores de Fármacos , Imidazóis/administração & dosagem , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/enzimologia , Nanopartículas , Polímeros/química , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Fármacos Cardiovasculares/química , Fármacos Cardiovasculares/metabolismo , Química Farmacêutica , Modelos Animais de Doenças , Composição de Medicamentos , Imidazóis/química , Imidazóis/metabolismo , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo , Regeneração/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
J Appl Physiol (1985) ; 110(5): 1460-5, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21292844

RESUMO

This study evaluates a therapy for infarct modulation and acute myocardial rescue and utilizes a novel technique to measure local myocardial oxygenation in vivo. Bone marrow-derived endothelial progenitor cells (EPCs) were targeted to the heart with peri-infarct intramyocardial injection of the potent EPC chemokine stromal cell-derived factor 1α (SDF). Myocardial oxygen pressure was assessed using a noninvasive, real-time optical technique for measuring oxygen pressures within microvasculature based on the oxygen-dependent quenching of the phosphorescence of Oxyphor G3. Myocardial infarction was induced in male Wistar rats (n = 15) through left anterior descending coronary artery ligation. At the time of infarction, animals were randomized into two groups: saline control (n = 8) and treatment with SDF (n = 7). After 48 h, the animals underwent repeat thoracotomy and 20 µl of the phosphor Oxyphor G3 was injected into three areas (peri-infarct myocardium, myocardial scar, and remote left hindlimb muscle). Measurements of the oxygen distribution within the tissue were then made in vivo by applying the end of a light guide to the beating heart. Compared with controls, animals in the SDF group exhibited a significantly decreased percentage of hypoxic (defined as oxygen pressure ≤ 15.0 Torr) peri-infarct myocardium (9.7 ± 6.7% vs. 21.8 ± 11.9%, P = 0.017). The peak oxygen pressures in the peri-infarct region of the animals in the SDF group were significantly higher than the saline controls (39.5 ± 36.7 vs. 9.2 ± 8.6 Torr, P = 0.02). This strategy for targeting EPCs to vulnerable peri-infarct myocardium via the potent chemokine SDF-1α significantly decreased the degree of hypoxia in peri-infarct myocardium as measured in vivo by phosphorescence quenching. This effect could potentially mitigate the vicious cycle of myocyte death, myocardial fibrosis, progressive ventricular dilatation, and eventual heart failure seen after acute myocardial infarction.


Assuntos
Quimiocina CXCL12/uso terapêutico , Medições Luminescentes/métodos , Metaloporfirinas/farmacocinética , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miocárdio/metabolismo , Oxigênio/metabolismo , Indutores da Angiogênese/uso terapêutico , Animais , Masculino , Infarto do Miocárdio/patologia , Ratos , Ratos Wistar , Distribuição Tecidual , Resultado do Tratamento
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