Abstract
A host of hormonal-metabolic alterations take place following exposure of cardiomyocytes to hypoxia and other noxious stimuli. Here, we demonstrate that exposure of cultured rat cardiomyocytes to lipopolysaccharide (LPS) resulted in upregulation (~1.5 fold) of oxidized low-density lipoprotein receptor-1 (LOX-1). There was also a marked increase in apoptosis 12 hrs after LPS treatment with caspase-3 levels being significantly elevated (~1.3 fold) and a significant increase in LDH release at 24 hrs. Interestingly, there was a ~1.4-fold upregulation of LC-3 expression post-LPS treatment indicating development of autophagy, which probably is a compensatory response to combat cellular injury induced by LPS. Treatment with LPS also reduced the size and morphology of cardiomyocyte spheroids. In an attempt to limit LPS-induced injury, cardiomyocytes were treated with exosomes derived from mesenchymal stromal cells (MSCs). We noted a significant suppression of LOX-1 expression that in turn suppressed apoptosis as well as autophagic response and restored spheroid morphology. Mass spectrophotometric analysis of MSC exosomes revealed a cargo rich in proteins which are involved in pathways negatively modulating cell death and apoptosis while promoting cell survival. This is first report to our knowledge on the initial molecular events in MSC exosome mediated cytoprotection of stressed cardiomyocytes.
Highlights
A host of hormonal-metabolic alterations take place following exposure of cardiomyocytes to hypoxia and other noxious stimuli
Scanning electron microscopy (SEM) analysis of suspended exosome pellet was used to confirm that the ultracentrifugation pellet isolated from mesenchymal stromal cells (MSCs) cultures consisted of discrete vesicles and not parts of damaged intracellular cellular organelles or membranes
These results along with electron micropictographs indicate that the pellets isolated from conditioned media of MSC cultures by sequential centrifugation constitute a distinct set of secretory vesicles
Summary
A host of hormonal-metabolic alterations take place following exposure of cardiomyocytes to hypoxia and other noxious stimuli. Mass spectrophotometric analysis of MSC exosomes revealed a cargo rich in proteins which are involved in pathways negatively modulating cell death and apoptosis while promoting cell survival. This is first report to our knowledge on the initial molecular events in MSC exosome mediated cytoprotection of stressed cardiomyocytes. Expression of LOX-1 appears to be important in the eventual determination of extent of ischemic myocardial injury[3,12,13,14], since abrogation of LOX-1 reduces infarct size, number of apoptotic cells, inflammatory signaling, ROS generation and cardiac function. We conducted proteomics to determine pathways of LPS-mediated cellular injury and their modulation by MSC exosomes
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