Abstract
BackgroundAutophagy plays a major role in myocardial ischemia and hypoxia injury. The present study investigated the effects of autophagy on cardiac dysfunction in rats after severe burn.MethodsProtein expression of the autophagy markers LC3 and Beclin 1 were determined at 0, 1, 3, 6, and 12 h post-burn in Sprague Dawley rats subjected to 30% total body surface area 3rd degree burns. Autophagic, apoptotic, and oncotic cell death were evaluated in the myocardium at each time point by immunofluorescence. Changes of cardiac function were measured in a Langendorff model of isolated heart at 6 h post-burn, and the autophagic response was measured following activation by Rapamycin and inhibition by 3-methyladenine (3-MA). The angiotensin converting enzyme inhibitor enalaprilat, the angiotensin receptor I blocker losartan, and the reactive oxygen species inhibitor diphenylene iodonium (DPI) were also applied to the ex vivo heart model to examine the roles of these factors in post-burn cardiac function.ResultsAutophagic cell death was first observed in the myocardium at 3 h post-burn, occurring in 0.008 ± 0.001% of total cardiomyocytes, and continued to increase to a level of 0.022 ± 0.005% by 12 h post-burn. No autophagic cell death was observed in control hearts. Compared with apoptosis, autophagic cell death occurred earlier and in larger quantities. Rapamycin enhanced autophagy and decreased cardiac function in isolated hearts 6 h post-burn, while 3-MA exerted the opposite response. Enalaprilat, losartan, and DPI all inhibited autophagy and enhanced heart function.ConclusionMyocardial autophagy is enhanced in severe burns and autophagic cell death occurred early at 3 h post-burn, which may contribute to post-burn cardiac dysfunction. Angiotensin II and reactive oxygen species may play important roles in this process by regulating cell signaling transduction.
Highlights
Autophagy plays a major role in the physiological cellular degradation and recycling of long-lived proteins and organelles, maintaining cellular homeostasis and adaptation to nutrient depletion [1]
Changes of Autophagy Marker Proteins To determine whether cardiac autophagy was enhanced under severe burn conditions, we examined for light chain 3 (LC3) and beclin 1 expression
Our results showed that the LC3 II/ LC3 I ratio significantly rose at 1 h post-burn in the myocardium, and the total level of LC3 proteins increased later at 3h postburn
Summary
Autophagy plays a major role in the physiological cellular degradation and recycling of long-lived proteins and organelles, maintaining cellular homeostasis and adaptation to nutrient depletion [1]. Autophagy represents a programmed and dynamic process that proceeds by sequestration of cellular material into double membrane vacuoles that dock to and fuse with lysosomes to form autophagic vacuoles (i.e. autophagosome), where the contents are degraded by lysosomal hydrolases and the resulting macromolecules are recycled [2]. Autophagy occurs at basal levels, but can be induced by stress conditions such as hypoxia or ischemia/reperfusion [4,5]. The ubiquitin/protein degradation system is associated with the autophagic machinery [8], ubiquitin expression in tissues can be used to determine autophagic cell death [9]. Autophagy plays a major role in myocardial ischemia and hypoxia injury. The present study investigated the effects of autophagy on cardiac dysfunction in rats after severe burn
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