Abstract
Inhibitors of the ubiquitin-proteasome system improve hemodynamic parameters and decrease the infarct size after ischemia reperfusion. The molecular basis of this protection is not fully understood since most available data report inhibition of the 26 proteasome after ischemia reperfusion. The decrease in cellular ATP levels during ischemia leads to the dissociation of the 26S proteasome into the 19S regulatory complex and the 20S catalytic core, which results in protein degradation independently of ubiquitination. There is scarce information on the activity of the 20S proteasome during cardiac ischemia. Accordingly, the aim of this work was to determine the effects of 30 minutes of ischemia, or 30 min of ischemia followed by 60 minutes of reperfusion on the three main peptidase activities of the 20S proteasome in Langendorff perfused rat hearts. We found that 30 min of ischemia produced a significant increase in the chymotrypsin-like activity of the proteasome, without changes in its caspase-like or trypsin-like activities. In contrast, all three activities were decreased upon reperfusion. Ixazomib, perfused before ischemia at a concentration that reduced the chymotrypsin-like activity to 50% of the control values, without affecting the other proteasomal activities, improved the hemodynamic parameters upon reperfusion and decreased the infarct size. Ixazomib also prevented the 50% reduction in RyR2 content observed after ischemia. The protection was lost, however, when simultaneous inhibition of chymotrypsin-like and caspase-like activities of the proteasome was achieved at higher concentration of ixazomib. Our results suggest that selective inhibition of chymotrypsin-like activity of the proteasome during ischemia preserves key proteins for cardiomyocyte function and exerts a positive impact on cardiac performance after reperfusion.
Highlights
Myocardial ischemia represents a severe cellular stress that triggers dramatic biochemical and metabolic changes in the heart
At the concentrations used in this work, neither ixazomib nor MG132, at 0.5 μmol/L, produce significant changes in hemodynamic parameters in control hearts, not subjected to ischemia (S1 Fig)
Our results show that thirty minutes of warm ischemia in isolated rat hearts causes the death of almost 40% of the heart and a poor recovery of hemodynamic parameters upon reperfusion
Summary
Myocardial ischemia represents a severe cellular stress that triggers dramatic biochemical and metabolic changes in the heart. The generation of reactive oxygen species (ROS) during ischemia [1,2,3] initiates the oxidation and modification of cellular proteins by lipid hydroperoxides [4] that eventually produce irreversible cell damage and death. Proteasomes are proteolytic complexes responsible for the degradation of over 90% of cellular proteins. Inhibition of the proteasome as a pharmacological strategy to prevent cell damage in ischemia reperfusion has produced conflicting results. Several studies report that the activity of the 26S proteasome decreases after ischemia reperfusion [9,10,11] and that further pharmacological inhibition produces more damage [12]. An increasing number of studies have shown that proteasome inhibitors protect the heart from IR damage [13,14,15,16]
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