The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction.
The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction.
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DOI：
10.7150/thno.19422
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发表时间：
2017
期刊：
影响因子：
12.4
通讯作者：
Pacella JJ
中科院分区：
文献类型：
--
作者：
Yu FTH;Chen X;Straub AC;Pacella JJ
理由：急性心肌梗死PCI术中微栓塞可引起微血管阻塞（MVO）。MVO严重限制了再灌注治疗的成功，与额外的肌坏死有关，并与包括死亡在内的较差预后有关。我们已经在体外和体内模型中表明，超声（US）和微泡（MB）治疗（称为“超声再灌注”或“SRP”）是一种缓解MVO和恢复灌注的治疗方法，但其潜在机制仍有待建立。目的：探讨一氧化氮（NO）在SRP中的作用。方法和结果：我们首先证明了在体外镀细胞中，us刺激的MB振荡诱导内皮一氧化氮合酶（eNOS）磷酸化增加6倍。然后，我们监测大鼠后肢肌肉在使用和不使用LNAME阻断eNOS的情况下，SRP治疗2分钟后肌肉内NO和灌注流率反应的动力学。在SRP后，我们发现从6分钟开始，肌肉内NO在30分钟内显著增加，在13分钟后高于基线。同时增强的爆发再灌注成像证实，与基线相比，SRP后6和10分钟的灌注流率明显增加（>2.5倍）。肌内NO和灌注率的增加被LNAME所抑制。最后，我们通过评估先前描述的大鼠后肢MVO模型在eNOS阻断期间的再灌注功效，验证了NO在SRP中起作用的假设。经US治疗1后，MB+US组微血管血容量恢复到基线，但LNAME组微血管血容量仍然较低。在US治疗后，MB+US组的灌注率增加，而MB+US+LNAME组则没有。结论：这些数据有力地支持MB振荡可以激活eNOS通路导致血流灌注增加，NO在SRP疗效中起重要作用。
Rationale: Microembolization during PCI for acute myocardial infarction can cause microvascular obstruction (MVO). MVO severely limits the success of reperfusion therapies, is associated with additional myonecrosis, and is linked to worse prognosis, including death. We have shown, both in in vitro and in vivo models, that ultrasound (US) and microbubble (MB) therapy (termed “sonoreperfusion” or “SRP”) is a theranostic approach that relieves MVO and restores perfusion, but the underlying mechanisms remain to be established. Objective: In this study, we investigated the role of nitric oxide (NO) during SRP. Methods and results: We first demonstrated in plated cells that US-stimulated MB oscillations induced a 6-fold increase in endothelial nitric oxide synthase (eNOS) phosphorylation in vitro. We then monitored the kinetics of intramuscular NO and perfusion flow rate responses following 2-min of SRP therapy in the rat hindlimb muscle, with and without blockade of eNOS with LNAME. Following SRP, we found that starting at 6 minutes, intramuscular NO increased significantly over 30 min and was higher than baseline after 13 min. Concomitant contrast enhanced burst reperfusion imaging confirmed that there was a marked increase in perfusion flow rate at 6 and 10 min post SRP compared to baseline (>2.5 fold). The increases in intramuscular NO and perfusion rate were blunted with LNAME. Finally, we tested the hypothesis that NO plays a role in SRP by assessing reperfusion efficacy in a previously described rat hindlimb model of MVO during blockade of eNOS. After US treatment 1, microvascular blood volume was restored to baseline in the MB+US group, but remained low in the LNAME group. Perfusion rates increased in the MB+US group after US treatment 2 but not in the MB+US+LNAME group. Conclusions: These data strongly support that MB oscillations can activate the eNOS pathway leading to increased blood perfusion and that NO plays a significant role in SRP efficacy.