Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.
Pulmonary Arterial Hypertension and Endothelial Dysfunction Is Linked to NADPH Oxidase-Derived Superoxide Formation in Venous Thrombosis and Pulmonary Embolism in Mice.
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DOI：
10.1155/2018/1860513
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发表时间：
2018
影响因子：
--
通讯作者：
Wenzel P
中科院分区：
文献类型：
--
作者：
Brandt M;Giokoglu E;Garlapati V;Bochenek ML;Molitor M;Hobohm L;Schönfelder T;Münzel T;Kossmann S;Karbach SH;Schäfer K;Wenzel P
肺动脉栓塞（PE）由深静脉血栓形成（DVT）引起，可导致慢性血栓栓塞性肺动脉高压（CTEPH），涉及血管功能障碍。机制尚不完全清楚，部分原因是缺乏小鼠模型。我们通过静脉注射凝血酶（166 U/kg BW）诱导C57BL/6小鼠PE，并通过高频超声观察到突发性心动过缓、呼吸急促和肺动脉（PA）压升高。虽然单次使用凝血酶后症状迅速缓解，但重复使用PEs导致持续的PA压力升高，通过氧化荧光微形貌评估PA超氧化物形成增加，PA gp91phox表达增加，24小时后通过离体PA段的等长张力研究评估内皮功能障碍。通过结扎下腔静脉（IVC），建立C57BL/6小鼠DVT模型。重要的是，在没有PA压力升高的情况下，可以检测到小肺栓塞，并伴有轻度PA内皮功能障碍和氧化应激表型。反复注射凝血酶后，复发性PE小鼠PAs中纤溶酶原激活物抑制剂-1 mRNA表达增加，而DVT小鼠的mRNA表达增加程度较小。总之，我们的数据表明，gp91phox来源的ROS诱导的PA内皮功能障碍是重复性PE的早期事件。这一现象可能有助于阐明PA功能障碍在CTEPH发病中的作用机制。
Pulmonary embolism (PE) results from deep vein thrombosis (DVT) and can lead to chronic thromboembolic pulmonary hypertension (CTEPH) involving vascular dysfunction. Mechanisms are incompletely understood, in part due to lack of mouse models. We induced PE in C57BL/6 mice by intravenous injection of thrombin (166 U/kg BW), confirmed by a sudden bradycardia, bradypnea, and an increase in pulmonary artery (PA) pressure observed by high-frequency ultrasound. While symptoms resolved rapidly after single thrombin application, repeated PEs resulted in sustained PA-pressure increase, increased PA superoxide formation assessed by oxidative fluorescent microtopography, increased PA gp91phox expression, and endothelial dysfunction assessed by isometric tension studies of isolated PA segments after 24 hours. DVT was modeled in C57BL/6 mice by ligation of the inferior vena cava (IVC). Importantly, small pulmonary emboli could be detected along with a mild phenotype of PA endothelial dysfunction and oxidative stress in the absence of PA-pressure elevation. mRNA expression of plasminogen activator inhibitor-1 was increased in PAs of mice with recurrent PE after repetitive thrombin injections and to a lesser extent in DVT mice. In summary, our data suggest that PA endothelial dysfunction, induced by gp91phox-derived ROS, is an early event upon repetitive PE. This phenomenon might help to elucidate the mechanisms of PA dysfunction in the pathogenesis of CTEPH.
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DOI：
10.1084/jem.20112322
发表时间：
2012-04-09
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
von Brühl ML;Stark K;Steinhart A;Chandraratne S;Konrad I;Lorenz M;Khandoga A;Tirniceriu A;Coletti R;Köllnberger M;Byrne RA;Laitinen I;Walch A;Brill A;Pfeiler S;Manukyan D;Braun S;Lange P;Riegger J;Ware J;Eckart A;Haidari S;Rudelius M;Schulz C;Echtler K;Brinkmann V;Schwaiger M;Preissner KT;Wagner DD;Mackman N;Engelmann B;Massberg S
通讯作者：
Massberg S
影响因子：
37.8
作者：
Temme, Sebastian;Grapentin, Christoph;Floegel, Ulrich
通讯作者：
Floegel, Ulrich
影响因子：
2.9
作者：
CHOMCZYNSKI, P;SACCHI, N
通讯作者：
SACCHI, N
影响因子：
6
作者：
Good, Robert B.;Gilbane, Adrian J.;Holmes, Alan M.
通讯作者：
Holmes, Alan M.
影响因子：
20.1
作者：
Diebold, Isabel;Djordjevic, Talija;Goerlach, Agnes
通讯作者：
Goerlach, Agnes