Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice.
OBJECTIVE
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.


RESULTS
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.


CONCLUSIONS
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.
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America ; Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, United States of America.
Terrence
T
Pong
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Marielle
M
Scherrer-Crosbie
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Dmitriy N
DN
Atochin
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Kenneth D
KD
Bloch
Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, United States of America ; School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts, United States of America ; Harvard-MIT Division of Health Sciences & Technology, Cambridge, Massachusetts, United States of America.
Paul L
PL
Huang
D000818:Animals; D003287:Contrast Media; D003326:Coronary Circulation; D004789:Enzyme Activation; D057775:Ischemic Postconditioning; D007700:Kinetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050505:Mutant Proteins / Q000378:metabolism*; D015425:Myocardial Reperfusion; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000201:enzymology* / Q000503:physiopathology / Q000517:prevention & control; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014463:Ultrasonography
D003287:Contrast Media; D050505:Mutant Proteins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D051057:Proto-Oncogene Proteins c-akt