The Heart Institute of Good Samaritan Hospital, Los Angeles, CA 90017, USA.
J Cardiovasc Pharmacol. 2012 Sep;60(3):276-82. doi: 10.1097/FJC.0b013e31825ea0fa.
We determined whether a small molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1-i) could reduce myocardial infarct size in a rat ischemia/reperfusion model.
Sprague-Dawley rats were randomized to 3 groups: ASK1-i infusion (n = 16), vehicle infusion (n = 16), or ischemic preconditioning (IPC; n = 15). Infusion of ASK1-i (10 mg/kg, iv) or vehicle commenced 45 minutes before myocardial ischemia. IPC consisted of 3 cycles of 3 minutes of coronary occlusion followed by 5 minutes of reperfusion immediately before index myocardial ischemia, which consisted of 30-minute left coronary occlusion followed by 180 minutes of reperfusion. Pathologic analysis revealed no significant difference in the ischemic risk size among the 3 groups. ASK1-I and IPC significantly reduced myocardial infarct size (27.7% ± 3.3%, 16.5% ± 3.4%, and 41.5% ± 4.8% in the ASK1-i group, the IPC group, and the vehicle group, respectively; P = 0.0002) and apoptosis (the percentage of apoptotic nuclei averaged 11.6% ± 1.0%, 10.2% ± 1.7%, and 17.7% ± 2.0% in the ASK1-i group, IPC group, and vehicle group, respectively, P = 0.0055).
A small molecule inhibitor of ASK1 was shown for the first time to reduce apoptosis and myocardial infarct size in a rat model of ischemia/reperfusion.
我们旨在确定凋亡信号调节激酶 1（ASK1）的小分子抑制剂是否能减少大鼠缺血/再灌注模型的心肌梗死面积。
将 Sprague-Dawley 大鼠随机分为 3 组：ASK1-i 输注组（n = 16）、载体输注组（n = 16）和缺血预处理组（IPC；n = 15）。ASK1-i（10 mg/kg，iv）或载体输注于心肌缺血前 45 分钟开始。IPC 包括 3 个循环的 3 分钟冠状动脉闭塞，然后在指数性心肌缺血前立即进行 5 分钟再灌注，指数性心肌缺血包括 30 分钟左冠状动脉闭塞和 180 分钟再灌注。病理分析显示 3 组之间的缺血危险面积没有显著差异。ASK1-i 和 IPC 显著减少心肌梗死面积（ASK1-i 组、IPC 组和载体组分别为 27.7% ± 3.3%、16.5% ± 3.4%和 41.5% ± 4.8%；P = 0.0002）和凋亡（凋亡核的百分比分别为 11.6% ± 1.0%、10.2% ± 1.7%和 17.7% ± 2.0%；ASK1-i 组、IPC 组和载体组；P = 0.0055）。
首次证明凋亡信号调节激酶 1 的小分子抑制剂可减少大鼠缺血/再灌注模型中的细胞凋亡和心肌梗死面积。
