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1.
Stem Cell Res ; 10(3): 301-12, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23399448

RESUMO

We have previously identified exosomes as the paracrine factor secreted by mesenchymal stem cells. Recently, we found that the key features of reperfusion injury, namely loss of ATP/NADH, increased oxidative stress and cell death were underpinned by proteomic deficiencies in ischemic/reperfused myocardium, and could be ameliorated by proteins in exosomes. To test this hypothesis in vivo, mice (C57Bl6/J) underwent 30 min ischemia, followed by reperfusion (I/R injury). Purified exosomes or saline was administered 5 min before reperfusion. Exosomes reduced infarct size by 45% compared to saline treatment. Langendorff experiments revealed that intact but not lysed exosomes enhanced viability of the ischemic/reperfused myocardium. Exosome treated animals exhibited significant preservation of left ventricular geometry and contractile performance during 28 days follow-up. Within an hour after reperfusion, exosome treatment increased levels of ATP and NADH, decreased oxidative stress, increased phosphorylated-Akt and phosphorylated-GSK-3ß, and reduced phosphorylated-c-JNK in ischemic/reperfused hearts. Subsequently, both local and systemic inflammation were significantly reduced 24h after reperfusion. In conclusion, our study shows that intact exosomes restore bioenergetics, reduce oxidative stress and activate pro-survival signaling, thereby enhancing cardiac function and geometry after myocardial I/R injury. Hence, mesenchymal stem cell-derived exosomes are a potential adjuvant to reperfusion therapy for myocardial infarction.


Assuntos
Trifosfato de Adenosina/metabolismo , Exossomos/metabolismo , Células-Tronco Mesenquimais/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Sobrevivência Celular , Células Cultivadas , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Coração/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Endogâmicos C57BL , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/citologia , Fosforilação , Transdução de Sinais , Remodelação Ventricular
2.
Int J Cardiovasc Imaging ; 29(2): 343-54, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22790331

RESUMO

Myocardial edema can arise in several disease states. MRI contrast agent can accumulate in edematous tissue, which complicates differential diagnosis with contrast-enhanced (CE)-MRI and might lead to overestimation of infarct size. Sodium Chemical Shift Imaging ((23)Na-CSI) may provide an alternative for edema imaging. We have developed a non-infarct, isolated rat heart model with two levels of edema, which was studied with (23)Na-CSI and CE-MRI. In edematous, but viable tissue the extracellular sodium (Na (e) (+)) signal is hypothesized to increase, but not the intracellular sodium (Na (i) (+)) signal. Isolated hearts were perfused at 60 (n = 6) and 140 mmHg (n = 5). Dimethyl methylphosphonate (DMMP) and phenylphosphonate (PPA) were used to follow edema formation by (31)P-MR Spectroscopy. In separate groups, Thulium(III)1,4,7,10 tetraazacyclododecane-N,N',N″,N'''-tetra(methylenephosphonate) (TmDOTP(5-)) and Gadovist were used for (23)Na-CSI (n = 8) and CE-MRI (n = 6), respectively. PPA normalized signal intensity (SI) was higher at 140 versus 60 mmHg, with a ratio of 1.27 ± 0.12 (p < 0.05). The (DMMP-PPA)/dry weight ratio, as a marker of intracellular volume, remained unchanged. The mid-heart cross sectional area (CSA) of the left ventricle (LV) was significantly increased at 140 mmHg. In addition, at 140 mmHg, the LV Na (e) (+) SI increased with a 140 mmHg/60 mmHg ratio of 1.24 ± 0.18 (p < 0.05). Na (i) (+) SI remained essentially unchanged. With CE-MRI, a subendocardially enhanced CSA was identified, increasing from 0.20 ± 0.02 cm(2) at 60 mmHg to 0.31 ± 0.02 cm(2) at 140 mmHg (p < 0.05). Edema shows up in both CE-MRI and Na (e) (+) . High perfusion pressure causes more edema subendocardially than subepicardially. (23)Na-CSI is an attractive alternative for imaging of edema and is a promising tool to discriminate between edema, acute and chronic MI.


Assuntos
Meios de Contraste , Edema Cardíaco/diagnóstico , Imageamento por Ressonância Magnética , Miocárdio/patologia , Compostos Organometálicos , Compostos Organofosforados , Isótopos de Sódio , Animais , Diagnóstico Diferencial , Edema Cardíaco/metabolismo , Edema Cardíaco/patologia , Técnicas In Vitro , Espectroscopia de Ressonância Magnética , Masculino , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Perfusão , Valor Preditivo dos Testes , Ratos , Ratos Wistar , Fatores de Tempo
3.
MAGMA ; 25(5): 369-79, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22327962

RESUMO

OBJECT: Imaging of myocardial infarct composition is essential to assess efficacy of emerging therapeutics. T (2) (*) mapping has the potential to image myocardial hemorrhage and fibrosis by virtue of its short T (2) (*) . We aimed to quantify T (2) (*) in acute and chronic myocardial ischemia/reperfusion (I/R) injury in mice. MATERIALS AND METHODS: I/R-injury was induced in C57BL/6 mice (n = 9). Sham-operated mice (n = 8) served as controls. MRI was performed at baseline, and 1, 7 and 28 days after surgery. MRI at 9.4 T consisted of Cine, T (2) (*) mapping and late-gadolinium-enhancement (LGE). Mice (n = 6) were histologically assessed for hemorrhage and collagen in the fibrotic scar. RESULTS: Baseline T (2) (*) values were 17.1 ± 2.0 ms. At day 1, LGE displayed a homogeneous infarct enhancement. T (2) (*) in infarct (12.0 ± 1.1 ms) and remote myocardium (13.9 ± 0.8 ms) was lower than at baseline. On days 7 and 28, LGE was heterogeneous. T (2) (*) in the infarct decreased to 7.9 ± 0.7 and 6.4 ± 0.7 ms, whereas T (2) (*) values in the remote myocardium were 14.2 ± 1.1 and 15.6 ± 1.0 ms. Histology revealed deposition of iron and collagen in parallel with decreased T (2) (*) . CONCLUSION: T (2) (*) values are dynamic during infarct development and decrease significantly during scar maturation. In the acute phase, T (2) (*) values in infarcted myocardium differ significantly from those in the chronic phase. T (2) (*) mapping was able to confirm the presence of a chronic infarction in cases where LGE was inconclusive. Hence, T (2) (*) may be used to discriminate between acute and chronic infarctions.


Assuntos
Imagem Cinética por Ressonância Magnética/métodos , Infarto do Miocárdio/patologia , Traumatismo por Reperfusão Miocárdica/patologia , Doença Aguda , Animais , Colágeno/química , Modelos Animais de Doenças , Fibrose/patologia , Ventrículos do Coração/patologia , Hemorragia/diagnóstico , Ferro/química , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/complicações , Miocárdio/patologia , Fatores de Tempo
4.
J Cell Mol Med ; 16(10): 2379-86, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22348515

RESUMO

Undesired cell migration after targeted cell transplantation potentially limits beneficial effects for cardiac regeneration. MicroRNAs are known to be involved in several cellular processes, including cell migration. Here, we attempt to reduce human cardiomyocyte progenitor cell (hCMPC) migration via increasing microRNA-155 (miR-155) levels, and investigate the underlying mechanism. Human cardiomyocyte progenitor cells (hCMPCs) were transfected with pre-miR-155, anti-miR-155 or control-miR (ctrl-miR), followed by scratch- and transwell-assays. These functional assays displayed that miR-155 over-expression efficiently inhibited cell migration by 38 ± 3.6% and 59 ± 3.7% respectively. Conditioned medium from miR-155 transfected cells was collected and zymography analysis showed a significant decrease in MMP-2 and MMP-9 activities. The predicted 3'-UTR of MMP-16, an activator of MMP-2 and -9, was cloned into the pMIR-REPORT vector and luciferase assays were performed. Introduction of miR-155 significantly reduced luciferase activity which could be abolished by cotransfection with anti-miR-155 or target site mutagenesis. By using MMP-16 siRNA to reduce MMP-16 levels or by using an MMP-16 blocking antibody, hCMPC migration could be blocked as well. By directly targeting MMP-16, miR-155 efficiently inhibits cell migration via a reduction in MMP-2 and -9 activities. Our study shows that miR-155 might be used to improve local retention of hCMPCs after intramyocardial delivery.


Assuntos
Movimento Celular , Metaloproteinase 16 da Matriz/metabolismo , MicroRNAs/metabolismo , Miócitos Cardíacos/citologia , Células-Tronco/metabolismo , Western Blotting , Proliferação de Células , Células Cultivadas , Clonagem Molecular , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Humanos , Imuno-Histoquímica , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/genética , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transfecção
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