Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo
Inhibition of RIP1-dependent necrosis prevents adverse cardiac remodeling after myocardial ischemia-reperfusion in vivo
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DOI：
10.1007/s00395-012-0270-8
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发表时间：
2012-07-01
影响因子：
9.5
通讯作者：
Sluijter, Joost P. G.
中科院分区：
文献类型：
--
作者：
Oerlemans, Martinus I. F. J.;Liu, Jia;Sluijter, Joost P. G.
越来越多的证据表明，程序性坏死在缺血再灌注过程中的细胞死亡中起着至关重要的作用。Necrostatin-1（Nec-1）是一种能够抑制程序性坏死（RIP 1）关键调节因子的小分子，在包括心肌缺血在内的实验模型中显示可预防坏死细胞死亡。然而，没有进行功能随访，Nec-1的作用仍不清楚。在这里，我们研究了Nec-1是否抑制RIP 1依赖性坏死，并导致体内缺血再灌注后的长期改善。小鼠经历30分钟的缺血，并在再灌注前5分钟接受3.3 mg/kg Nec-1或载体治疗，随后再灌注。Nec-1给药将梗死面积减少至26.3 +/-1.3%（P = 0.001），相比之下，载体治疗的动物中为38.6 +/-1.7%。此外，Nec-1在体内抑制RIP 1/RIP 3磷酸化并显著减少坏死性细胞死亡，而凋亡性细胞死亡保持恒定。通过使用MRI，评估手术前和手术后28天的心脏尺寸和功能。Nec-1治疗的小鼠表现出较少的不良重塑（舒张末期容积63.5 +/- 2.8对74.9 +/- 2.8 μ l，P = 0.031）和保留的心脏性能（射血分数45.81 +/- 2.05对36.03 +/-2.37%，P = 0.016）。Nec-1治疗显著降低了炎症内流、肿瘤坏死因子-α mRNA水平和氧化应激水平。有趣的是，这伴随着氧化应激基因表达特征的显著变化。在再灌注开始时给予Nec-1抑制体内RIP 1依赖性坏死，导致梗死面积减小和心脏功能保留。Nec-1的心脏保护作用突出了缺血性心脏中坏死细胞死亡的重要性，从而为心肌梗死患者的治疗开辟了新的方向。
Accumulating evidence indicates that programmed necrosis plays a critical role in cell death during ischemia-reperfusion. Necrostatin-1 (Nec-1), a small molecule capable of inhibiting a key regulator of programmed necrosis (RIP1), was shown to prevent necrotic cell death in experimental models including cardiac ischemia. However, no functional follow-up was performed and the action of Nec-1 remains unclear. Here, we studied whether Nec-1 inhibits RIP1-dependent necrosis and leads to long-term improvements after ischemia-reperfusion in vivo. Mice underwent 30 min of ischemia and received, 5 min before reperfusion, 3.3 mg/kg Nec-1 or vehicle treatment, followed by reperfusion. Nec-1 administration reduced infarct size to 26.3 +/- 1.3 % (P = 0.001) compared to 38.6 +/- 1.7 % in vehicle-treated animals. Furthermore, Nec-1 inhibited RIP1/RIP3 phosphorylation in vivo and significantly reduced necrotic cell death, while apoptotic cell death remained constant. By using MRI, cardiac dimensions and function were assessed before and 28 days after surgery. Nec-1-treated mice displayed less adverse remodeling (end-diastolic volume 63.5 +/- 2.8 vs. 74.9 +/- 2.8 mu l, P = 0.031) and preserved cardiac performance (ejection fraction 45.81 +/- 2.05 vs. 36.03 +/- 2.37 %, P = 0.016). Nec-1 treatment significantly reduced inflammatory influx, tumor necrosis factor-alpha mRNA levels and oxidative stress levels. Interestingly, this was accompanied by significant changes in the expression signature of oxidative stress genes. Administration of Nec-1 at the onset of reperfusion inhibits RIP1-dependent necrosis in vivo, leading to infarct size reduction and preservation of cardiac function. The cardioprotective effect of Nec-1 highlights the importance of necrotic cell death in the ischemic heart, thereby opening a new direction for therapy in patients with myocardial infarction.