Endothelial nitric oxide synthase overexpression attenuates myocardial reperfusion injury.
Previous studies indicate that deficiency of endothelial nitric oxide (NO) synthase (eNOS)-derived NO exacerbates myocardial reperfusion injury. We hypothesized that overexpression of eNOS would reduce the extent of myocardial ischemia-reperfusion (MI/R) injury. We investigated two distinct strains of transgenic (TG) mice overexpressing the eNOS gene (eNOS TG). Bovine eNOS was overexpressed in one strain (eNOS TG-Kobe), whereas the human eNOS gene was overexpressed in the other strain (eNOS TG-RT). Non-TG (NTG) and eNOS TG mice were subjected to 30 min of coronary artery occlusion followed by 24 h of reperfusion, and the extent of myocardial infarction was determined. Myocardial infarct size was reduced by 33% in the eNOS TG-Kobe strain (P < 0.05 vs. NTG) and by 32% in the eNOS TG-RT strain (P < 0.05 vs. NTG). However, postischemic cardiac function (cardiac output, fractional shortening) was not improved in the eNOS TG-Kobe mouse at 24 h of reperfusion [P = not significant (NS) vs. NTG]. In additional studies, eNOS TG-Kobe mice were subjected to 30 min of myocardial infarction and 7 days of reperfusion. Fractional shortening and the first derivative of left ventricular pressure were measured in eNOS TG-Kobe and NTG mice, and no significant differences in contractility were observed (P = NS) between the eNOS TG mice and NTG controls. Left ventricular end-diastolic pressure was significantly (P < 0.05 vs. NTG) reduced in the eNOS TG-Kobe strain at 7 days of reperfusion. The cardioprotective effects of eNOS overexpression on myocardial infarct size were ablated by Nomega-nitro-l-arginine methyl ester (300 mg/kg) pretreatment. Thus genetic overexpression of eNOS in mice attenuates myocardial infarction after MI/R but fails to significantly protect against postischemic myocardial contractile dysfunction in mice.
Jones
Steven P
SP
Department of Molecular and Cellular Physiology, LSU Health Sciences Center, 1501 Kings Highway, Shreveport, LA 71130, USA.
Greer
James J M
JJ
Kakkar
Aman K
AK
Ware
P Derek
PD
Turnage
Richard H
RH
Hicks
Michael
M
van Haperen
Rien
R
de Crom
Rini
R
Kawashima
Seinosuke
S
Yokoyama
Mitsuhiro
M
Lefer
David J
DJ
D000475:Alkenes / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D003652:Decanoic Acids / Q000494:pharmacology; D004452:Echocardiography; D006321:Heart / Q000503:physiopathology; D006439:Hemodynamics; D006801:Humans; D006880:Hydroxy Acids / Q000494:pharmacology; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000473:pathology; D017202:Myocardial Ischemia / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D015428:Myocardial Reperfusion Injury / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D013997:Time Factors
D000475:Alkenes; D003652:Decanoic Acids; D006880:Hydroxy Acids; D020030:Nitric Oxide Donors; C453079:dipropylenetriamine-NONOate; C052853:5-hydroxydecanoic acid; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse