Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1
Celastrol protects ischaemic myocardium through a heat shock response with up-regulation of haeme oxygenase-1
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DOI：
10.1111/bph.12838
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发表时间：
2014-12-01
影响因子：
7.3
通讯作者：
Noiseux, N.
中科院分区：
文献类型：
--
作者：
Der Sarkissian, S.;Cailhier, J-F;Noiseux, N.
背景与目的南蛇藤酚是一种植物源三萜类化合物，在传统的东方医药中被用于治疗多种疾病。在这里，我们研究了雷公藤红素对缺血的心脏保护作用。实验方法雷公藤红素诱导的保护途径进行了研究，在缺氧培养的H9 c2大鼠心肌细胞和大鼠模型的心肌梗死，评估与超声心动图和组织学分析。关键结果在H9 c2细胞，雷公藤红素触发活性氧簇（ROS）的形成在几分钟内，诱导转录因子热休克因子1（HSF 1）的核转位，导致热休克反应（HSR），导致热休克蛋白（HSP）的表达增加。ROS清除剂N-乙酰半胱氨酸减少HSP 70和HSP 32（血红素加氧酶-1，HO-1）的表达。雷公藤红素改善H9 c2在缺氧应激下的存活，功能分析显示HSF 1和HO-1是雷公藤红素诱导的HSR在促进细胞保护中的关键效应子。在大鼠缺血心肌中，雷公藤红素治疗在14天时改善了心脏功能并减少了不良的左心室重构。南蛇藤酚触发心脏保护HO-1的表达，并抑制纤维化和梗死面积。在梗死周围区域，雷公藤红素减少肌成纤维细胞和巨噬细胞浸润，同时减弱TGF-β和胶原基因的上调。结论和ImplicationsCelastrol治疗诱导HSR通过激活HSF 1与上调HO-1作为关键效应，促进心肌细胞存活，减少损伤和不良重塑与保存心脏功能。雷公藤红素可能代表一种新型的有效的药理学心脏保护剂，模拟缺血条件，可能对心肌梗死的治疗产生有价值的影响。
Background and PurposeCelastrol, a triterpene from plants, has been used in traditional oriental medicine to treat various diseases. Here, we investigated the cardioprotective effects of celastrol against ischaemia.Experimental ApproachProtective pathways induced by celastrol were investigated in hypoxic cultures of H9c2 rat cardiomyoblasts and in a rat model of myocardial infarction, assessed with echocardiographic and histological analysis.Key ResultsIn H9c2 cells, celastrol triggered reactive oxygen species (ROS) formation within minutes, induced nuclear translocation of the transcription factor heat shock factor 1 (HSF1) resulting in a heat shock response (HSR) leading to increased expression of heat shock proteins (HSPs). ROS scavenger N-acetylcysteine reduced expression of HSP70 and HSP32 (haeme oxygenase-1, HO-1). Celastrol improved H9c2 survival under hypoxic stress, and functional analysis revealed HSF1 and HO-1 as key effectors of the HSR, induced by celastrol, in promoting cytoprotection. In the rat ischaemic myocardium, celastrol treatment improved cardiac function and reduced adverse left ventricular remodelling at 14 days. Celastrol triggered expression of cardioprotective HO-1 and inhibited fibrosis and infarct size. In the peri-infarct area, celastrol reduced myofibroblast and macrophage infiltration, while attenuating up-regulation of TGF- and collagen genes.Conclusions and ImplicationsCelastrol treatment induced an HSR through activation of HSF1 with up-regulation of HO-1 as the key effector, promoting cardiomyocyte survival, reduction of injury and adverse remodelling with preservation of cardiac function. Celastrol may represent a novel potent pharmacological cardioprotective agent mimicking ischaemic conditioning that could have a valuable impact in the treatment of myocardial infarction.