Soluble receptor for advanced glycation end-products protects against ischemia/reperfusion-induced myocardial apoptosis via regulating the ubiquitin proteasome system.
Soluble receptor for advanced glycation end-products protects against ischemia/reperfusion-induced myocardial apoptosis via regulating the ubiquitin proteasome system.
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DOI：
10.1016/j.freeradbiomed.2016.02.011
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发表时间：
2016-05
影响因子：
7.4
通讯作者：
Caixia Guo;Xue Jiang;Xiang-jun Zeng;Hong-Xia Wang;Hui-Hua Li;F. Du;Bu-xing Chen
中科院分区：
文献类型：
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作者：
Caixia Guo;Xue Jiang;Xiang-jun Zeng;Hong-Xia Wang;Hui-Hua Li;F. Du;Bu-xing Chen
[目的]细胞凋亡参与心肌缺血再灌注损伤的病理过程。已有研究报道内源性物质SRAGE通过抑制心肌细胞凋亡对I/R损伤具有保护作用。但机制目前尚不清楚。前期研究表明，泛素蛋白酶体系统(UPS)功能障碍与细胞凋亡密切相关。方法与结果成年雄性C57BL小鼠给予SRAGE(100g/d，μ)灌胃治疗。或生理盐水结扎左冠状动脉前降支(LAD)作为活体模型。以SRAGE或携带SRAGE的腺病毒处理原代小鼠心肌细胞作为体外模型，用“缺血缓冲液”模拟心肌细胞的I/R。检测TUNEL和caspase-3活性。同时检测蛋白酶体的活性和表达。SRAGE可减少心肌细胞TUNEL阳性细胞数和caspase-3活性，但这种抑制作用可被蛋白酶体抑制剂Bortezimb(BTZ)阻断。SRAGE可抑制I/R后蛋白酶体活性的降低以及β1i和β5i蛋白和基因水平的降低。抑制STAT3可阻断SRAGE对I/R诱导的细胞凋亡的抑制作用。染色质免疫沉淀(ChIP)结果证实，SRAGE可促进激活STAT3与β1i和β5i启动子的结合。结论SRAGE抑制I/R诱导的细胞凋亡与蛋白酶体的激活和表达有关，包括提高蛋白酶体活性和上调β1i和β5i的表达。我们预测，SRAGE是一种针对UPS激活以预防和治疗心肌细胞凋亡的新干预措施。
AimApoptosis participated in the pathological process of myocardial ischemia/reperfusion (I/R) injury. Previous studies have reported that endogenous substance sRAGE protect against I/R injury through inhibiting myocardial apoptosis. But the mechanisms are currently unknown. Prior work has demonstrated that ubiquitin proteasome system (UPS) dysfunction is closely related to apoptosis. We explored the potential role of UPS in the effect of sRAGE inhibition on I/R-induced myocardial apoptosis.Methods and resultsAdult male C57BL mice treated with sRAGE (100 μg/day, i.p.) or saline were performed to ligate left anterior descending coronary artery (LAD) as anin vivomodel. As anin vitromodel, primary murine cardiomyocytes pretreated with sRAGE or sRAGE-containing adenovirus were simulated I/R by “ischemia buffer”. The TUNEL and caspase-3 activity were assessed. Also the activity and expression of proteasome were detected. sRAGE decreased the number of TUNEL-positive cardiomyocytes and caspase-3 activity, however, the inhibition of sRAGE on I/R-induced apoptosis was abolished by proteasome inhibitor Bortezimb (BTZ). sRAGE inhibited the decreased proteasome activity, also the reduction in protein and gene levels of β1i and β5i following I/R. Suppression of STAT3 blocked the inhibition of sRAGE on apoptosis induced by I/R. The chromatin immunoprecipitation (CHIP) results confirmed that sRAGE promoted activating STAT3 binding to β1i and β5i promoter.ConclusionsOur data suggest that the inhibition of sRAGE on I/R-induced apoptosis is associated with activation and expression of proteasome, including improved proteasome activity and elevated β1i and β5i expression mediated by STAT3 activation. We predict that sRAGE is a novel intervention to target UPS activation for preventing and treating myocardial apoptosis.