Partial inhibition of the ubiquitin-proteasome system ameliorates cardiac dysfunction following ischemia-reperfusion in the presence of high glucose.
Partial inhibition of the ubiquitin-proteasome system ameliorates cardiac dysfunction following ischemia-reperfusion in the presence of high glucose.
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DOI：
10.1186/s12933-015-0258-4
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发表时间：
2015-07-28
影响因子：
9.3
通讯作者：
Essop MF
中科院分区：
文献类型：
--
作者：
Adams B;Mapanga RF;Essop MF
急性高血糖与心肌梗塞（在糖尿病和非糖尿病个体中）并存通常与不良预后相关。尽管急性高血糖会引起氧化应激，从而导致泛素蛋白酶体系统 (UPS) 失调，但尚不清楚在这种情况下 UPS 的增加/减少是否对缺血再灌注有害。由于我们早期的数据表明 UPS 与心脏损伤有关，我们假设它的抑制会导致在模拟急性高血糖条件下进行缺血再灌注时的心脏保护作用。使用含有 33 mM 葡萄糖与对照（11 mM 葡萄糖）的 Krebs-Henseleit 缓冲液进行离体大鼠心脏灌注，稳定 60 分钟，然后分别进行 20 分钟全局缺血和 60 分钟再灌注 ± 5 µM 乳胞素和 10 µM MG-132。在再灌注阶段的前 20 分钟内添加 UPS 抑制剂，并评估各种心脏功能参数。在平行实验中，在 20 分钟局部缺血和 120 分钟再灌注 ± 每种 UPS 抑制剂（在再灌注期间添加）后评估梗死面积。收集心脏组织并分析氧化应激、UPS 激活、炎症和自噬的标志物。这里使用的蛋白酶体抑制剂剂量和治疗持续时间导致再灌注阶段期间部分 UPS 抑制。在我们的实验系统中，lactacystin 和 MG-132 给药均能产生心脏保护作用，其中 MG-132 效果更好。蛋白酶体抑制剂还增强心脏超氧化物歧化酶蛋白水平（SOD1、SOD2），减弱促炎作用并导致自噬标记物上调。这项研究证实，部分蛋白酶体抑制可对暴露于缺血再灌注和急性模拟高血糖的心脏产生心脏保护作用。这些数据表明，蛋白酶抑制引发了三种主要的保护作用，即（a）增强心肌抗氧化防御，（b）减轻炎症，以及（c）增加自噬反应。因此，UPS 成为这种情况下治疗缺血性心脏病的独特治疗靶点。
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 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. 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.