Most studies on ischemic preconditioning (IPC) use one or two ischemic stimuli, before examining cardioprotection. In order to better simulate the clinical situation, we examined, in pigs, the effects of 6 episodes of 10 min coronary artery occlusion (CAO) 12 hours apart, followed by 60 min CAO. We named this model the 4th window of IPC. In order to determine the novel mechanisms mediating cardioprotection in the 4th window, gene analysis was examined in 4th window IPC cardiac tissue, 60 min after the last episode of 10 min CAO. Secreted Frizzled Related Protein 3 (sFRP3) was the most significantly upregulated gene that was unique to the 4th window, i.e., not found in the 1st, 2nd or 3rd window IPC. To study the effects of sFRP3 on cardioprotection, sFRP3 was injected in the hearts of WT mice. In the CAO/CAR model (30 min CAO followed by 24 hour CAR), infarct size was less, p<0.01, after sFRP3 injection (14±1.7%) compared to vehicle injection (48±1.6%). sFRP3 injection also protected the development of heart failure following permanent CAO for 2 wks. Left ventricular ejection fraction was significantly improved, p<0.05, at 2 weeks after CAO with sFRP3 (53±5%) compared with vehicle (36±2%), and was accompanied by significant, p<0.01, reductions in myocardial fibrosis (53±4%), myocyte size (17±3%), apoptosis (100%) and mortality (56%). Thus, sFRP3, unique to the clinically relevant 4th window IPC model, is a novel mechanism mediating ischemic cardioprotection.

中文翻译：

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分泌性卷曲蛋白 3 是一种新颖的心脏保护机制，是临床相关的缺血预处理第四窗口所独有的


大多数缺血预处理（IPC）研究在检查心脏保护作用之前都会使用一种或两种缺血刺激。为了更好地模拟临床情况，我们在猪身上检查了间隔 12 小时 6 次 10 分钟冠状动脉闭塞 (CAO) 的效果，然后进行 60 分钟 CAO。我们将这个模型命名为IPC的第四窗口。为了确定在第四窗口中介导心脏保护的新机制，在最后一次 10 分钟 CAO 发作后 60 分钟，在第四窗口 IPC 心脏组织中检查了基因分析。分泌性卷曲相关蛋白3 (sFRP3)是第四窗口所特有的最显着上调的基因，即在第一、第二或第三窗口IPC中未发现的基因。为了研究 sFRP3 对心脏保护的影响，将 sFRP3 注射到 WT 小鼠的心脏中。在 CAO/CAR 模型中（30 分钟 CAO，随后 24 小时 CAR），与媒介物注射后 (48±1.6%) 相比，注射 sFRP3 后 (14±1.7%) 梗塞面积更小 (p<0.01)。 sFRP3 注射还可以在 2 周内保护永久性 CAO 后心力衰竭的发展。与媒介物 (36±2%) 相比，CAO 后 2 周，使用 sFRP3 (53±5%) 的左心室射血分数显着改善 (p<0.05)，并且伴随着心肌纤维化显着 (p<0.01) 减少。 53±4%)、肌细胞大小(17±3%)、细胞凋亡(100%)和死亡率(56%)。因此，sFRP3是临床相关的第四窗口IPC模型所独有的，是介导缺血性心脏保护的新机制。