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1.
Circulation ; 134(13): 961-977, 2016 09 27.
Artigo em Inglês | MEDLINE | ID: mdl-27582424

RESUMO

BACKGROUND: Survival after sudden cardiac arrest is limited by postarrest myocardial dysfunction, but understanding of this phenomenon is constrained by a lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. METHODS: We developed rodent models of in vivo postarrest myocardial dysfunction using extracorporeal membrane oxygenation resuscitation followed by invasive hemodynamics measurement. In postarrest isolated cardiomyocytes, we assessed mechanical load and Ca(2) (+)-induced Ca(2+) release (CICR) simultaneously using the microcarbon fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel fiberoptic catheter imaging system and a genetically encoded calcium sensor, GCaMP6f, to image CICR in vivo. RESULTS: We found potentiation of CICR in isolated cells from this extracorporeal membrane oxygenation model and in cells isolated from an ischemia/reperfusion Langendorff model perfused with oxygenated blood from an arrested animal but not when reperfused in saline. We established that CICR potentiation begins in vivo. The augmented CICR observed after arrest was mediated by the activation of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban, and ryanodine receptor 2 was detected in the postarrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Because oxidative stress and aldehydic adduct formation were high after arrest, we tested a small-molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and postarrest outcome in vivo. CONCLUSIONS: Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term potentiation, which support cardiomyocyte contractility in the face of impaired postarrest myofilament calcium sensitivity. Alda-1 mitigates these effects, normalizes calcium cycling, and improves outcome.


Assuntos
Aldeído Desidrogenase/metabolismo , Benzamidas/farmacologia , Benzodioxóis/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Cálcio/metabolismo , Parada Cardíaca/fisiopatologia , Potenciação de Longa Duração/efeitos dos fármacos , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Cardiomiopatias/tratamento farmacológico , Cardiomiopatias/metabolismo , Potenciação de Longa Duração/fisiologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Retículo Sarcoplasmático/metabolismo
2.
Proc Natl Acad Sci U S A ; 110(50): 20218-23, 2013 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-24284176

RESUMO

The endocytic Ashwell-Morell receptor (AMR) of hepatocytes detects pathogen remodeling of host glycoproteins by neuraminidase in the bloodstream and mitigates the lethal coagulopathy of sepsis. We have investigated the mechanism of host protection by the AMR during the onset of sepsis and in response to the desialylation of blood glycoproteins by the NanA neuraminidase of Streptococcus pneumoniae. We find that the AMR selects among potential glycoprotein ligands unmasked by microbial neuraminidase activity in pneumococcal sepsis to eliminate from blood circulation host factors that contribute to coagulation and thrombosis. This protection is attributable in large part to the rapid induction of a moderate thrombocytopenia by the AMR. We further show that neuraminidase activity in the blood can be manipulated to induce the clearance of AMR ligands including platelets, thereby preactivating a protective response in pneumococcal sepsis that moderates the severity of disseminated intravascular coagulation and enables host survival.


Assuntos
Receptor de Asialoglicoproteína/imunologia , Hepatócitos/imunologia , Sepse/prevenção & controle , Streptococcus pneumoniae/imunologia , Análise de Variância , Animais , Receptor de Asialoglicoproteína/metabolismo , Tempo de Sangramento , Plaquetas/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Neuraminidase/administração & dosagem , Neuraminidase/metabolismo , Sepse/imunologia , Sepse/microbiologia
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