Abstract
ObjectiveMyocardial 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.Methods and ResultsWe 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.Conclusions and SignificanceUsing 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.
Highlights
Ischemic postconditioning is a modified form of reperfusion that results in reduced myocardial tissue damage [1,2]
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
Summary
Ischemic postconditioning is a modified form of reperfusion that results in reduced myocardial tissue damage [1,2]. The mechanisms underlying cardioprotection from postconditioning and preconditioning have been reviewed recently [3,4,5,6,7], and involve adenosine receptor signaling, and activation of pro-survival kinase pathways including ERK1/2, Akt/PI3 kinase, and STAT3. These pathways result in cellular changes, including activation of mitochondrial ATPdependent K channels and inhibition of mitochondrial permeability transition pore opening, resulting in reduction in tissue damage. A direct role for eNOS in modulating regional myocardial blood flow during reperfusion has not been demonstrated
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