U955-IMRB, Equipe 03, Inserm, UPEC, Ecole Nationale Vétérinaire d'Alfort, Maisons-Alfort, France.
Université de Montpellier, Inserm, CNRS, CHRU Montpellier, Montpellier, France.
Theranostics. 2020 Mar 4;10(9):4006-4016. doi: 10.7150/thno.40461. eCollection 2020.
Sonic hedgehog (SHH) signaling pathway is involved in embryonic tissue patterning and development. Our previous work identified, in small rodent model of ischemia reperfusion, SHH as a specific efficient tool to reduce infarct size and subsequent arrhythmias by preventing ventricular repolarization abnormalities. The goal of the present study was to provide a proof of concept of the cardioprotective effect of SHH ligand in a porcine model of acute ischemia. : The antiarrhythmic effect of SHH, either by a recombinant peptide (N-SHH) or shed membrane microparticles harboring SHH ligand (MPs), was evaluated in a first set of pigs following a short (25 min) coronary artery occlusion (CAO) followed by 24 hours-reperfusion (CAR) (Protocol A). The infarct-limiting effect was evaluated on a second set of pigs with 40 min of coronary artery occlusion followed by 24 hours reperfusion (Protocol B). Electrocardiogram (ECG) was recorded and arrhythmia's scores were evaluated. Area at risk and myocardial infarct size were quantified. : In protocol A, administration of N-SHH 15 min. after the onset of coronary occlusion significantly reduced the occurrence of ventricular fibrillation compared to control group. Evaluation of arrhythmic score showed that N-SHH treatment significantly reduced the overall occurrence of arrhythmias. In protocol B, massive infarction was observed in control animals. Either N-SHH or MPs treatment reduced significantly the infarct size with a concomitant increase of salvaged area. The reduction in infarct size was both accompanied by a significant decrease in systemic biomarkers of myocardial injury, i.e., cardiac troponin I and fatty acid-binding protein and an increase of eNOS activation. : We show for the first time in a large mammalian model that the activation of the SHH pathway by N-SHH or MPs offers a potent protection of the heart to ischemia-reperfusion by preventing the reperfusion arrhythmias, reducing the infarct area and the circulating levels of biomarkers for myocardial injury. These data open up potentially theranostic prospects for patients suffering from myocardial infarction to prevent the occurrence of arrhythmias and reduce myocardial tissue damage.
Sonic hedgehog (SHH) 信号通路参与胚胎组织形态发生和发育。我们之前的工作在小型啮齿动物缺血再灌注模型中发现，SHH 是一种通过防止心室复极化异常减少梗死面积和随后心律失常的特定有效工具。本研究的目的是在急性缺血的猪模型中提供 SHH 配体的心脏保护作用的概念验证。
在第一组猪中，在短暂（25 分钟）冠状动脉闭塞（CAO）后 24 小时再灌注（CAR）（方案 A）中，评估了 SHH 配体的重组肽（N-SHH）或释放膜微粒（MPs）对心律失常的抗心律失常作用。在第二组猪中，评估了 40 分钟冠状动脉闭塞后 24 小时再灌注（方案 B）的梗死限制作用。记录心电图（ECG）并评估心律失常评分。危险区和心肌梗死面积进行量化。
在方案 A 中，在冠状动脉闭塞开始后 15 分钟给予 N-SHH 可显著减少与对照组相比室颤的发生。心律失常评分评估表明，N-SHH 治疗显著降低了心律失常的总体发生率。在方案 B 中，在对照组动物中观察到大面积梗死。N-SHH 或 MPs 治疗均显著减少梗死面积，同时增加存活区。梗死面积的减少伴有心肌损伤的系统生物标志物即肌钙蛋白 I 和脂肪酸结合蛋白的显著降低以及 eNOS 激活的增加。
我们首次在大型哺乳动物模型中表明，通过 N-SHH 或 MPs 激活 SHH 通路可通过防止再灌注心律失常、减少梗死面积和循环中心肌损伤生物标志物的水平，为缺血再灌注提供心脏的有力保护。这些数据为患有心肌梗死的患者提供了潜在的治疗和诊断前景，以预防心律失常的发生并减少心肌组织损伤。
