Simultaneous Inhibition of Thrombosis and Inflammation Is Beneficial in Treating Acute Myocardial Infarction.
Simultaneous Inhibition of Thrombosis and Inflammation Is Beneficial in Treating Acute Myocardial Infarction.
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DOI：
10.3390/ijms24087333
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发表时间：
2023-04-15
影响因子：
5.6
通讯作者：
Pan, Hua
中科院分区：
文献类型：
--
作者：
Vargas, Ian;Grabau, Ryan P.;Chen, Junjie;Weinheimer, Carla;Kovacs, Attila;Dominguez-Viqueira, William;Mitchell, Adam;Wickline, Samuel A.;Pan, Hua
关键词：
急性冠状动脉综合征中的心肌缺血再灌注损伤（IRI）是一种尽管血栓性阻塞成功解决，但对闭塞血管对向的细胞的缺血/缺氧损伤持续的病症。几十年来，大多数减轻IRI的努力都集中在阻断单一的分子靶点或途径上，但没有一个成功地过渡到临床应用。在这项工作中，我们研究了一种基于纳米颗粒的治疗策略，用于深刻但局部的凝血酶抑制，可以同时减轻血栓形成和炎症信号通路，以限制心肌IRI。将全氟碳纳米颗粒（PFC NP）与不可逆凝血酶抑制剂PPACK（Phe[D]-Pro-Arg-Chloromethylketone）共价偶联，并在缺血再灌注损伤之前以单剂量静脉内递送至动物。组织切片的荧光显微镜检查和离体全心脏的19 F磁共振图像显示PFC NP大量递送到风险区域。再灌注后24 h的超声心动图显示心室结构保留，功能改善。治疗减少凝血酶沉积，抑制内皮细胞活化，抑制炎性体信号通路，并限制梗死边缘区的微血管损伤和血管修剪。因此，用非常有效但局部作用的药物抑制凝血酶表明凝血酶在心脏IRI中的关键作用和有希望的治疗策略。
Myocardial ischemia reperfusion injury (IRI) in acute coronary syndromes is a condition in which ischemic/hypoxic injury to cells subtended by the occluded vessel continues despite successful resolution of the thrombotic obstruction. For decades, most efforts to attenuate IRI have focused on interdicting singular molecular targets or pathways, but none have successfully transitioned to clinical use. In this work, we investigate a nanoparticle-based therapeutic strategy for profound but local thrombin inhibition that may simultaneously mitigate both thrombosis and inflammatory signaling pathways to limit myocardial IRI. Perfluorocarbon nanoparticles (PFC NP) were covalently coupled with an irreversible thrombin inhibitor, PPACK (Phe[D]-Pro-Arg-Chloromethylketone), and delivered intravenously to animals in a single dose prior to ischemia reperfusion injury. Fluorescent microscopy of tissue sections and 19F magnetic resonance images of whole hearts ex vivo demonstrated abundant delivery of PFC NP to the area at risk. Echocardiography at 24 h after reperfusion demonstrated preserved ventricular structure and improved function. Treatment reduced thrombin deposition, suppressed endothelial activation, inhibited inflammasome signaling pathways, and limited microvascular injury and vascular pruning in infarct border zones. Accordingly, thrombin inhibition with an extraordinarily potent but locally acting agent suggested a critical role for thrombin and a promising therapeutic strategy in cardiac IRI.
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影响因子：
10.6
作者：
Downs KP;Nguyen H;Dorfleutner A;Stehlik C
通讯作者：
Stehlik C
影响因子：
3.1
作者：
KERINS, DM
通讯作者：
KERINS, DM
影响因子：
4.3
作者：
Cohn, Claudia S.;Cushing, Melissa M.
通讯作者：
Cushing, Melissa M.
影响因子：
9.3
作者：
Dixon, Jennifer A.;Spinale, Francis G.
通讯作者：
Spinale, Francis G.
白介素-1和炎性体作为心血管疾病的治疗靶标。
影响因子：
20.1
作者：
Abbate A;Toldo S;Marchetti C;Kron J;Van Tassell BW;Dinarello CA
通讯作者：
Dinarello CA