Cardiovascular diabetology

Partial inhibition of the ubiquitin-proteasome system ameliorates cardiac dysfunction following ischemia-reperfusion in the presence of high glucose.

PMID 26216448


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. Ex vivo rat heart perfusions were performed with Krebs-Henseleit buffer containing 33xa0mM glucose vs. controls (11xa0mM glucose) for 60xa0min stabilization, followed by 20xa0min global ischemia and 60xa0min reperfusionxa0±xa05xa0µM lactacystin and 10xa0µM MG-132, respectively. The UPS inhibitors were added during the first 20xa0min of the reperfusion phase and various cardiac functional parameters evaluated. In parallel experiments, infarct sizes were assessed following 20xa0min regional ischemia and 120xa0min reperfusionxa0±xa0each of the respective UPS inhibitors (added during reperfusion). Heart tissues were collected and analyzed for markers of oxidative stress, UPS activation, inflammation and autophagy. 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. 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.