Necrostatin: a potentially novel cardioprotective agent?

来自掌桥科研

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107

作者：

CCT Smith，SM Davidson，SY Lim，JC Simpkin，JS Hothersall，DM Yellon

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摘要：

Background Necrostatin-1 (Nec-1), a small tryptophan-based molecule, was recently reported to protect the cerebral cortex against ischemia-reperfusion (I/R) injury. We investigated the actions of Nec-1 and its so-called inactive analog, Nec-1i, in the setting of myocardial I/R injury. Materials and methods The actions of Nec-1 and Nec-1i were examined in cultured C2C12 and H9c2 myocytes, cardiomyocytes isolated from male Sprague–Dawley rats, Langendorff isolated perfused C57Bl/6J mouse hearts and an in vivo open-chest C57Bl/6J mouse heart model. Results Nec-1 at 30μM and 100μM (but not 100μM Nec-1i) reduced peroxide-induced cell death in C2C12 cells from 51.2±1.1% (control) to 26.3±2.9% ( p <0.01 vs control) and 17.8±0.9% ( p <0.001), respectively. With H9c2 cells cell death was also reduced from 73.0±0.4% (control) to 56.7±0% (30μM Nec-1, p <0.05) and 45.4±3.3% (100μM Nec-1, p <0.01). In the isolated perfused heart Nec-1 (30μM) reduced infarct size (calculated as a percentage of the risk area) from 48.0±2.0% (control) to 32.1±5.4% ( p <0.05). Nec-1i (30μM) also reduced infarct size (32.9±5.1%, p <0.05). In anesthetized C57Bl/6J mice Nec-1 (1.65mg/kg), given intraperitoneally to coincide with reperfusion following left anterior descending artery ligation (30min), also reduced infarct size from 45.3±5.1% (control) to 26.6±4.0% ( p <0.05), whilst Nec-1i (1.74mg/kg) was ineffective (37.8±6.0%). Stimulus-induced opening of the mitochondrial permeability transition pore ( MPTP ) in rat cardiomyocytes, as reflected by the time until mitochondrial depolarisation, was unaffected by Nec-1 or Nec-1i at 30μM but increased at 100μM i.e. 91% ( p <0.05 vs control) and 152% ( p <0.001) for Nec-1 and Nec-1i, respectively. Conclusion This is the first study to demonstrate that necrostatins inhibit myocardial cell death and reduce infarct size, possibly via a mechanism independent of the MPTP .

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关键词：

necrostatin cardioprotection infarct size mitochondrial permeability transition pore

DOI：

10.1007/s10557-007-6035-1

被引量：

646

年份：

2007