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Myocardial ischemia-reperfusion injury is exacerbated in absence of endothelial cell nitric oxide synthase
S P Jones1, W G Girod, A J Palazzo
1Department of Molecular and Cellular Physiology, Louisiana State University Medical Center, Shreveport, Louisiana 71130-3392, USA.
Abstract:
Myocardial ischemia and reperfusion (MI/R) initiates a cascade of polymorphonuclear neutrophil (PMN)-mediated injury, the magnitude of which may be influenced by the bioavailability of nitric oxide (NO). We investigated the role of endothelial cell nitric oxide synthase (ecNOS) in MI/R injury by subjecting wild-type and ecNOS-deficient (-/-) mice to 20 min of coronary artery occlusion and 120 min of reperfusion. Myocardial infarct size represented 20.9 +/- 2.9% of the ischemic zone in wild-type mice, whereas the ecNOS -/- mice had significantly (P < 0.01) larger infarcts measuring 46.0 +/- 3.8% of the ischemic zone. Because P-selectin is thought to be involved with the pathogenesis of neutrophil-mediated I/R injury, we assessed the effects of MI/R on P-selectin expression in the myocardium of wild-type and ecNOS -/- mice. P-selectin expression measured with a radiolabeled monoclonal antibody (MAb) technique after MI/R in wild-type mice was 0.037 +/- 0.009 microgram MAb/g tissue, whereas ecNOS -/- coronary vasculature was characterized by significantly (P < 0.05) higher P-selectin expression (0.080 +/- 0.013 microgram MAb/g tissue). Histological examination of the postischemic myocardium revealed significantly (P < 0.01) more neutrophils in the ecNOS -/- (29.5 +/- 2.5 PMN/field) compared with wild-type (5.0 +/- 0.9 PMN/field) mice. A similar trend in infarct size and neutrophil accumulation was observed when wild-type and ecNOS -/- mice were subjected to 30 min of ischemia and 120 min of reperfusion. These novel in vivo findings demonstrate a cardioprotective role for ecNOS-derived NO in the ischemic-reperfused mouse heart.
Insights
Endothelial cell nitric oxide synthase (ecNOS) protects the heart during ischemia and reperfusion injury. Mice lacking ecNOS had larger heart infarcts and more neutrophil accumulation, indicating ecNOS-derived nitric oxide (NO) is cardioprotective.
Area of Science:
- Cardiovascular Research
- Molecular Medicine
- Inflammation Biology
Background:
- Myocardial ischemia and reperfusion (MI/R) injury involves neutrophil-mediated damage.
- The role of nitric oxide (NO) bioavailability in modulating this injury is not fully understood.
- Endothelial cell nitric oxide synthase (ecNOS) is a key source of NO in the vasculature.
Purpose of the Study:
- To investigate the role of ecNOS in myocardial ischemia and reperfusion (MI/R) injury.
- To determine if ecNOS-derived NO influences neutrophil infiltration and infarct size.
- To assess the impact of ecNOS deficiency on P-selectin expression during MI/R.
Main Methods:
- Subjected wild-type and ecNOS-deficient mice to coronary artery occlusion and reperfusion.
- Quantified myocardial infarct size using histological analysis.
- Measured P-selectin expression in the myocardium via a radiolabeled monoclonal antibody technique.
- Assessed neutrophil accumulation in the postischemic myocardium via histological examination.
Main Results:
- ecNOS-deficient mice exhibited significantly larger infarct sizes (46.0%) compared to wild-type mice (20.9%).
- P-selectin expression was significantly higher in the coronary vasculature of ecNOS-deficient mice post-MI/R.
- Histological analysis revealed significantly greater neutrophil infiltration in ecNOS-deficient mice compared to wild-type mice.
Conclusions:
- ecNOS plays a crucial cardioprotective role in the setting of myocardial ischemia and reperfusion.
- ecNOS-derived NO appears to mitigate neutrophil-mediated injury during MI/R.
- Targeting ecNOS or its downstream NO signaling may offer therapeutic strategies for MI/R injury.