Partial inhibition of the ubiquitin– proteasome system ameliorates cardiac dysfunction following ischemia–reperfusion in the presence of high glucose
Date
2015
Journal Title
Journal ISSN
Volume Title
Publisher
Springer Verlag
Abstract
Abstract
Background: Acute hyperglycemia co-presenting with myocardial infarction (in diabetic and non-diabetic individuals)
is often associated with a poor prognosis. Although acute hyperglycemia induces oxidative stress that can lead to
dysregulation of the ubiquitin–proteasome system (UPS), it is unclear whether increased/decreased UPS is detrimental
with ischemia–reperfusion under such conditions. As our earlier data implicated the UPS in cardiac damage, we
hypothesized that its inhibition results in cardioprotection with ischemia–reperfusion performed under conditions
that simulate acute hyperglycemia.
Methods: Ex vivo rat heart perfusions were performed with Krebs–Henseleit buffer containing 33 mM glucose vs.
controls (11 mM glucose) for 60 min stabilization, followed by 20 min global ischemia and 60 min reperfusion ± 5 µM
lactacystin and 10 µM MG-132, respectively. The UPS inhibitors were added during the first 20 min of the reperfusion
phase and various cardiac functional parameters evaluated. In parallel experiments, infarct sizes were assessed
following 20 min regional ischemia and 120 min reperfusion ± each of the respective UPS inhibitors (added during
reperfusion). Heart tissues were collected and analyzed for markers of oxidative stress, UPS activation, inflammation
and autophagy.
Results: The proteasome inhibitor doses and treatment duration here employed resulted in partial UPS inhibition
during the reperfusion phase. Both lactacystin and MG-132 administration resulted in cardioprotection in our
experimental system, with MG-132 showing a greater effect. The proteasome inhibitors also enhanced cardiac
superoxide dismutase protein levels (SOD1, SOD2), attenuated pro-inflammatory effects and caused an upregulation
of autophagic markers.
Conclusions: This study established that partial proteasome inhibition elicits cardioprotection in hearts exposed
to ischemia–reperfusion with acute simulated hyperglycemia. These data reveal that protease inhibition triggered
three major protective effects, i.e. (a) enhancing myocardial anti-oxidant defenses, (b) attenuating inflammation, and
(c) increasing the autophagic response. Thus the UPS emerges as a unique therapeutic target for the treatment of
ischemic heart disease under such conditions.
Keywords: Ubiquitin–proteasome system, Ischemia–reperfusion, Cardiac dysfunction, Hyperglycemia, Inflammation,
Oxidative stress, Autophagy
Description
Keywords
Ubiquitin–proteasome system,, schemia–reperfusion, Cardiac dysfunction, Hyperglycemia, Inflammation, Oxidative stress, Autophagy
Citation
Adams, B., Mapanga, R.F., & Essop, M.F. 2015. Partial inhibition of the ubiquitin– proteasome system ameliorates cardiac dysfunction following ischemia–reperfusion in the presence of high glucose. Cardiovascular Diabetology, 14(94), DOI 10.1186/s12933-015-0258-4