Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice.
Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice.
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DOI：
10.1371/journal.pone.0085946
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Huang PL
中科院分区：
文献类型：
--
作者：
Pong T;Scherrer-Crosbie M;Atochin DN;Bloch KD;Huang PL
心肌缺血再灌注损伤导致的心肌梗死可以通过心脏后处理来减少，在心脏后处理中，血流在完全再灌注之前间歇性地恢复。虽然参与后处理的关键分子机制和促生存途径已经确定，但eNOS衍生的NO在改善局部心肌灌注中的直接作用尚未显示。本研究的目的是测量，具有高的时间和空间分辨率，局部心肌灌注在缺血再灌注和后处理，以确定区域血流的影响，NO梗死面积和保护的贡献。我们使用心肌造影超声心动图来测量小鼠随时间推移的局部心肌血流量。心肌缺血-再灌注损伤后的再灌注可通过后处理和拟磷酸化eNOS调节得到改善。敲入表达eNOS的磷酸化模拟物S1176 D形式的小鼠表现出改善的心肌再灌注和显著减小的梗死面积。eNOS基因敲除小鼠未能表现出心脏保护作用。缺血-再灌注后无复流区的大小通过后处理和拟磷酸化eNOS突变而显著减小。使用心肌造影超声心动图，我们发现局部心肌灌注恢复的时间动态有助于后处理后梗死面积的减少。eNOS对缺血-再灌注后的心肌血流具有直接作用，使无复流区的大小减小。这些结果对正在进行的心脏保护临床试验具有重要意义，因为保护益处的程度可能受到eNOS衍生的NO的局部血流动力学效应的显著影响。
Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock-in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no-reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO.
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DOI：
10.1152/ajpheart.1999.276.5.h1567
发表时间：
1999-05-01
影响因子：
4.8
作者：
Jones, SP;Girod, WG;Lefer, DJ
通讯作者：
Lefer, DJ
影响因子：
4.3
作者：
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通讯作者：
Ovize, Michel
DOI：
10.1016/s0894-7317(00)70004-6
发表时间：
2000-05-01
影响因子：
6.5
作者：
Scherrer-Crosbie, M;Liel-Cohen, N;Picard, MH
通讯作者：
Picard, MH
影响因子：
64.8
作者：
Dimmeler, S;Fleming, I;Zeiher, AM
通讯作者：
Zeiher, AM
影响因子：
37.8
作者：
Raher, Michael J.;Thibault, Helene;Scherrer-Crosbie, Marielle
通讯作者：
Scherrer-Crosbie, Marielle