Inhibition of the proteasome preserves Mitofusin-2 and mitochondrial integrity, protecting cardiomyocytes during ischemia-reperfusion injury.

Cardiomyocyte loss is the main cause of myocardial dysfunction following an ischemia-reperfusion (IR) injury. Mitochondrial dysfunction and altered mitochondrial network dynamics play central roles in cardiomyocyte death. Proteasome inhibition is cardioprotective in the setting of IR; however, the mechanisms underlying this protection are not well-understood. Several proteins that regulate mitochondrial dynamics and energy metabolism, including Mitofusin-2 (Mfn2), are degraded by the proteasome. The aim of this study was to evaluate whether proteasome inhibition can protect cardiomyocytes from IR damage by maintaining Mfn2 levels and preserving mitochondrial network integrity. Using ex vivo Langendorff-perfused rat hearts and in vitro neonatal rat ventricular myocytes, we showed that the proteasome inhibitor MG132 reduced IR-induced cardiomyocyte death. Moreover, MG132 preserved mitochondrial mass, prevented mitochondrial network fragmentation, and abolished IR-induced reductions in Mfn2 levels in heart tissue and cultured cardiomyocytes. Interestingly, Mfn2 overexpression also prevented cardiomyocyte death. This effect was apparently specific to Mfn2, as overexpression of Miro1, another protein implicated in mitochondrial dynamics, did not confer the same protection. Our results suggest that proteasome inhibition protects cardiomyocytes from IR damage. This effect could be partly mediated by preservation of Mfn2 and therefore mitochondrial integrity.

Policistina-1 protege a los cardiomiocitos de la necrosis inducida por estrés mecánico / Policystin-1 protects cardiomyocytes from mechanical stress induced necrosis

Resumen: Antecedentes: La muerte de los cardiomiocitos es determinante en el desarrollo de patologías cardiacas posteriores al infarto del miocardio y la insuficiencia cardiaca. Las variaciones en la expresión de la familia de proteínas BCL-2 regulan vías, tanto de muerte, como de sobrevida celular. Así, BCL-2 es una proteína anti- apoptótica y NIX una proteína que induce la necrosis y/o la apoptosis celular. La Policistina-1 (PC1) es un mecanosensor vital para la función contráctil cardiaca; sin embargo, se desconoce su papel en la sobrevida de los cardiomiocitos durante el estrés mecánico. Objetivo: Determinar si PC-1 previene la muerte de los cardiomiocitos inducida por estrés mecánico y las proteínas BCL-2 y NIX. Métodos: Se utilizó cultivo de cardiomiocitos de ratas neonatas controles o deficientes en la expresión de PC1, estimulados con solución hiposmótica (HS), como modelo de estrés mecánico. Se midió la muerte por necrosis y apoptosis y los niveles de BCL-2 y NIX. Resultados: La deficiencia de la PC1 en los cardiomiocitos induce un aumento de la necrosis y los niveles proteicos de NIX en las células estimuladas con HS. El estrés mecánico induce la apoptosis basal relacionada a una disminución de BCL- 2, independiente de la expresión de la PC1. Conclusiones: La PC1 protege a los cardiomiocitos de la necrosis por estrés mecánico, lo que podría deberse en parte a su papel en la regulación de los niveles de las proteínas NIX.

Abstracts: Background: Cardiomyocytes death is a determining factor in the development of cardiac dysfunction after myocardial infarction and heart failure. The change in BCL-2 family protein expression regulates both cell death and survival pathways, whereas BCL-2 is an anti-apoptotic protein and NIX induces necrosis and/or apoptosis. Polycystin-1 (PC1) is a crucial mechanosensor for cardiac contractile function. However, its role in cardiomyocyte survival during mechanical stress is unknown. Aim: To study the relationship of PC1 with mechanical stretch-death in cardiomyocytes and the BCL-2, and NIX proteins. Methods. Controls or deficient expression of PC1 neonatal rat ventricular myocytes were stimulated with hypoosmotic solution (HS) and used as a model of mechanical stress. Necrosis or apoptosis cell death, BCL-2 and NIX protein levels were measured. Results: Deficient expression of PC1 increases cardiomyocyte necrosis and NIX protein levels in cells stimulated with HS. Mechanical stress induces basal apoptosis related to a decrease in BCL-2, independent of PC1 expression. Conclusion: PC1 protects cardiomyocytes from mechanical stress necrosis, at least in part, by regulating NIX protein levels.

Disfunción muscular respiratoria: una entidad multicausal en el paciente críticamente enfermo sometido a ventilación mecánica / Respiratory Muscle Dysfunction: A Multicausal Entity in the Critically Ill Patient Undergoing Mechanical Ventilation

Es probable que la disfunción de los músculos respiratorios, principalmente del diafragma, constituya una pieza clave dentro de los mecanismos fisiopatológicos que conducen a la dificultad del destete de la ventilación mecánica. La limitada movilidad del paciente crítico -y en especial del diafragma- cuando se requiere soporte prolongado con ventilación mecánica favorece el inicio temprano de la disfunción muscular respiratoria, la cual puede originarse también o hacerse mayor en presencia de factores frecuentes en el paciente críticamente enfermo, tales como sepsis, desnutrición, edad avanzada, duración y modo ventilatorio, uso de algunos medicamentos como glucocorticoides y bloqueadores neuromusculares. En esta revisión haremos énfasis en este origen multicausal, en el que la alteración del metabolismo de las proteínas es un mecanismo común involucrado, de acuerdo con los hallazgos reportados en diferentes modelos. El entendimiento de esta multicausalidad integrada por un mismo mecanismo fisiopatológico podría favorecer el manejo y la monitorización de los pacientes sometidos a ventilación mecánica

Respiratory muscle dysfunction, particularly of the diaphragm, may play a key role in the pathophysiological mechanisms that lead to difficulty in weaning patients from mechanical ventilation. The limited mobility of critically ill patients, and of the diaphragm in particular when prolonged mechanical ventilation support is required, promotes the early onset of respiratory muscle dysfunction, but this can also be caused or exacerbated by other factors that are common in these patients, such as sepsis, malnutrition, advanced age, duration and type of ventilation, and use of certain medications, such as steroids and neuromuscular blocking agents. In this review we will study in depth this multicausal origin, in which a common mechanism is altered protein metabolism, according to the findings reported in various models. The understanding of this multicausality produced by the same pathophysiological mechanism could facilitate the management and monitoring of patients undergoing mechanical ventilation

Respiratory muscle dysfunction: a multicausal entity in the critically ill patient undergoing mechanical ventilation.

Respiratory muscle dysfunction, particularly of the diaphragm, may play a key role in the pathophysiological mechanisms that lead to difficulty in weaning patients from mechanical ventilation. The limited mobility of critically ill patients, and of the diaphragm in particular when prolonged mechanical ventilation support is required, promotes the early onset of respiratory muscle dysfunction, but this can also be caused or exacerbated by other factors that are common in these patients, such as sepsis, malnutrition, advanced age, duration and type of ventilation, and use of certain medications, such as steroids and neuromuscular blocking agents. In this review we will study in depth this multicausal origin, in which a common mechanism is altered protein metabolism, according to the findings reported in various models. The understanding of this multicausality produced by the same pathophysiological mechanism could facilitate the management and monitoring of patients undergoing mechanical ventilation.