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1.
Am J Cardiol ; 105(10): 1371-1377.e1, 2010 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-20451681

RESUMO

Acute myocardial infarction (AMI) initiates an intense inflammatory response in which interleukin-1 (IL-1) plays a central role. The IL-1 receptor antagonist is a naturally occurring antagonist, and anakinra is the recombinant form used to treat inflammatory diseases. The aim of the present pilot study was to test the safety and effects of IL-1 blockade with anakinra on left ventricular (LV) remodeling after AMI. Ten patients with ST-segment elevation AMI were randomized to either anakinra 100 mg/day subcutaneously for 14 days or placebo in a double-blind fashion. Two cardiac magnetic resonance (CMR) imaging and echocardiographic studies were performed during a 10- to 14-week period. The primary end point was the difference in the interval change in the LV end-systolic volume index (LVESVi) between the 2 groups on CMR imaging. The secondary end points included differences in the interval changes in the LV end-diastolic volume index, and C-reactive protein levels. A +2.0 ml/m(2) median increase (interquartile range +1.0, +11.5) in the LVESVi on CMR imaging was seen in the placebo group and a -3.2 ml/m(2) median decrease (interquartile range -4.5, -1.6) was seen in the anakinra group (p = 0.033). The median difference was 5.2 ml/m(2). On echocardiography, the median difference in the LVESVi change was 13.4 ml/m(2) (p = 0.006). Similar differences were observed in the LV end-diastolic volume index on CMR imaging (7.6 ml/m(2), p = 0.033) and echocardiography (9.4 ml/m(2), p = 0.008). The change in C-reactive protein levels between admission and 72 hours after admission correlated with the change in the LVESVi (R = +0.71, p = 0.022). In conclusion, in the present pilot study of patients with ST-segment elevation AMI, IL-1 blockade with anakinra was safe and favorably affected by LV remodeling. If confirmed in larger trials, IL-1 blockade might represent a novel therapeutic strategy to prevent heart failure after AMI.


Assuntos
Proteína Antagonista do Receptor de Interleucina 1/administração & dosagem , Infarto do Miocárdio/complicações , Disfunção Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos , Adulto , Análise Química do Sangue , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Ecocardiografia , Feminino , Seguimentos , Hospitais Universitários , Humanos , Mediadores da Inflamação/análise , Injeções Subcutâneas , Interleucina-1/análise , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Projetos Piloto , Probabilidade , Valores de Referência , Medição de Risco , Resultado do Tratamento , Remodelação Ventricular/fisiologia , Virginia
2.
J Cardiovasc Pharmacol ; 55(4): 385-90, 2010 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-20125030

RESUMO

BACKGROUND: Myeloid differentiation factor 88 (MyD88) is an endogenous adaptor protein that coordinates the inflammatory response to agonists of the Toll-like receptor and interleukin-1 receptor families. This particular response is activated following myocardial ischemia and infarction and may represent a viable target for pharmacologic inhibition. The current study tested MyD88 inhibitors in a murine model of nonreperfused acute myocardial infarction (AMI). METHODS: AMI was induced by permanent ligation of the left coronary artery. Adult, male, Imprinting Control Region mice were randomized to daily injections with 1 of 2 MyD88 pharmacologic inhibitors (ST2825 25 mg/kg or IMG2005 1 mg/kg), saline, or pretreatment with MyD88-targeted silencing small interfering RNA (siRNA) or scrambled nontargeted siRNA (n = 6 for each group). Echocardiography was performed at baseline and 7 days after surgery to evaluate pathologic cardiac enlargement. RESULTS: Pharmacologic inhibition of MyD88 with ST2825 or IMG2005) and MyD88-targeted siRNA protected against left ventricular (LV) dilatation (reduced LV end-systolic and LV end-diastolic diameter) and hypertrophy. This protection occurred despite no measurable reduction in infarct size. CONCLUSIONS: Pharmacologic MyD88 inhibition protects against pathologic LV remodeling without altering infarct scar formation. MyD88 may be a viable target for pharmacologic inhibition in AMI.


Assuntos
Ventrículos do Coração/patologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Infarto do Miocárdio/terapia , Animais , Coração/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Compostos Heterocíclicos com 2 Anéis/farmacologia , Compostos Heterocíclicos com 2 Anéis/uso terapêutico , Hipertrofia Ventricular Esquerda/patologia , Interleucina-1beta/farmacologia , Interleucina-6/sangue , Masculino , Camundongos , Camundongos Endogâmicos ICR , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miocárdio/metabolismo , Miocárdio/patologia , NF-kappa B/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/uso terapêutico , Compostos de Espiro/farmacologia , Compostos de Espiro/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos
3.
Int J Angiol ; 19(4): e135-6, 2010.
Artigo em Inglês | MEDLINE | ID: mdl-22479145

RESUMO

Femoral pseudoaneurysm is a complication of cardiac catheterization and may be related to the use of anticoagulants, antiplatelet agents, larger diameter sheaths and prolonged duration of sheath insertion. The treatment ranges from direct compression with or without direct thrombin injection to surgical repair. The present report describes a unique scenario of postcardiac catheterization femoral artery pseudoaneursym in a patient with a pre-existing mechanical mitral valve requiring anticoagulation. The potential systemic effects of thrombin made the patient reluctant to undergo treatment and made thrombin administration a challenging proposition. The present report suggests that thrombin injection for treating femoral pseudoaneursym in patients with mechanical heart valves on chronic anticoagulation can be performed safely.

4.
J Neurosci ; 25(15): 3801-12, 2005 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-15829632

RESUMO

Parkinson's disease (PD) is linked genetically to proteins that function in the management of cellular stress resulting from protein misfolding and oxidative damage. Overexpression or mutation of alpha-synuclein results in the formation of Lewy bodies and neurodegeneration of dopaminergic (DA) neurons. Human torsinA, mutations in which cause another movement disorder termed early-onset torsion dystonia, is highly expressed in DA neurons and is also a component of Lewy bodies. Previous work has established torsins as having molecular chaperone activity. Thus, we examined the ability of torsinA to manage cellular stress within DA neurons of the nematode Caenorhabditis elegans. Worm DA neurons undergo a reproducible pattern of neurodegeneration after treatment with 6-hydroxydopamine (6-OHDA), a neurotoxin commonly used to model PD. Overexpression of torsins in C. elegans DA neurons results in dramatic suppression of neurodegeneration after 6-OHDA treatment. In contrast, expression of either dystonia-associated mutant torsinA or combined overexpression of wild-type and mutant torsinA yielded greatly diminished neuroprotection against 6-OHDA. We further demonstrated that torsins seem to protect DA neurons from 6-OHDA through downregulating protein levels of the dopamine transporter (DAT-1) in vivo. Additionally, we determined that torsins protect robustly against DA neurodegeneration caused by overexpression of alpha-synuclein. Using mutant nematodes lacking DAT-1 function, we also showed that torsin neuroprotection from alpha-synuclein-induced degeneration occurs in a manner independent of this transporter. Together, these data have mechanistic implications for movement disorders, because our results demonstrate that torsin proteins have the capacity to manage sources of cellular stress within DA neurons.


Assuntos
Dopamina/metabolismo , Regulação da Expressão Gênica/fisiologia , Chaperonas Moleculares/farmacologia , Degeneração Neural/prevenção & controle , Neurônios , Adrenérgicos/toxicidade , Análise de Variância , Animais , Animais Geneticamente Modificados , Western Blotting , Caenorhabditis elegans , Transportador 2 de Aminoácidos Catiônicos/toxicidade , Contagem de Células/métodos , Modelos Animais de Doenças , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Interações Medicamentosas , Embrião de Mamíferos , Embrião não Mamífero , Imunofluorescência/métodos , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/biossíntese , Humanos , Chaperonas Moleculares/genética , Mutagênese/fisiologia , Degeneração Neural/induzido quimicamente , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Oxidopamina/toxicidade , Fatores de Tempo , alfa-Sinucleína/metabolismo
6.
Hum Mol Genet ; 12(3): 307-19, 2003 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-12554684

RESUMO

Torsion dystonia is an autosomal dominant movement disorder characterized by involuntary, repetitive muscle contractions and twisted postures. The most severe early-onset form of dystonia has been linked to mutations in the human DYT1 (TOR1A) gene encoding a protein termed torsinA. While causative genetic alterations have been identified, the function of torsin proteins and the molecular mechanism underlying dystonia remain unknown. Phylogenetic analysis of the torsin protein family indicates these proteins share distant sequence similarity with the large and diverse family of AAA+ proteins. We have established the nematode, Caenorhabditis elegans, as a model system for examining torsin activity. Using an in vivo assay for polyglutamine repeat-induced protein aggregation in living animals, we have determined that ectopic overexpression of both human and C. elegans torsin proteins results in a dramatic reduction of polyglutamine-dependent protein aggregation in a manner similar to that previously reported for molecular chaperones. The suppressive effects of torsin overexpression persisted as animals aged, whereas a mutant nematode torsin protein was incapable of ameliorating aggregate formation. Antibody staining of transgenic animals indicated that both the C. elegans torsin-related protein TOR-2 and ubiquitin were localized to sites of protein aggregation. These data represent the first functional evidence of a role for torsins in effectively managing protein folding and suggest that possible breakdown in a neuroprotective mechanism that is, in part, mediated by torsins may be responsible for the neuronal dysfunction associated with dystonia.


Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/metabolismo , Peptídeos/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Proteínas/metabolismo , Envelhecimento , Sequência de Aminoácidos , Animais , Proteínas de Caenorhabditis elegans/biossíntese , Proteínas de Caenorhabditis elegans/genética , Modelos Animais de Doenças , Distonia/genética , Distonia/metabolismo , Chaperonas Moleculares/metabolismo , Dados de Sequência Molecular , Mutação , Fosfotransferases (Aceptor do Grupo Álcool)/biossíntese , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Alinhamento de Sequência
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