Cardiomyocyte-specific overexpression of NO synthase-3 protects against myocardial ischemia-reperfusion injury.
OBJECTIVE
The protective effect of NO synthase-3 (eNOS)-derived NO in limiting myocardial ischemia-reperfusion (MI-R) injury is well established. We reported previously that systemic genetic overexpression of eNOS attenuates MI-R injury. The purpose of the current study was to investigate tissue-specific genetic overexpression of the human eNOS gene.


RESULTS
To accomplish this, we used 2 distinct murine models of transgenic overexpression, a cardiomyocyte-specific eNOS overexpresser (CS eNOS-Tg) under the control of the alpha-myosin heavy chain promoter, and a systemic eNOS transgenic mouse (SYS eNOS-Tg) under control of the native eNOS promoter with an upstream endothelial enhancer element. Mice were subjected to 30 or 45 minutes of left coronary artery ischemia and 24 or 72 hours of reperfusion. CS eNOS-Tg mice displayed significantly decreased infarct size beyond that of mice with systemic overexpression. Additionally, CS eNOS-Tg mice exhibited better preservation of cardiac function compared with SYS eNOS-Tg mice after myocardial infarction.


CONCLUSIONS
These results provide evidence that site-specific targeting of eNOS gene therapy may be more advantageous in limiting MI-R injury and subsequent cardiac dysfunction.
Elrod
John W
JW
Department of Medicine, Division of Cardiology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA.
Greer
James J M
JJ
Bryan
Nathan S
NS
Langston
Will
W
Szot
Jeffrey F
JF
Gebregzlabher
Henock
H
Janssens
Stefan
S
Feelisch
Martin
M
Lefer
David J
DJ
D000818:Animals; D004452:Echocardiography; D018390:Gene Targeting; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III