Myocardial depression is an important contributor to morbidity and mortality in septic patients.
Nitric oxide (NO) plays an important role in the development of septic
cardiomyopathy, but also has protective effects. Recent evidence has indicated that NO exerts many of its downstream effects on the cardiovascular system via
protein S-nitrosylation, which is negatively regulated by
S-nitrosoglutathione reductase (GSNOR), an
enzyme promoting denitrosylation. We tested the hypothesis that reducing cardiomyocyte S-nitrosylation by increasing GSNOR activity can improve myocardial dysfunction during
sepsis. Therefore, we generated mice with a cardiomyocyte-specific overexpression of GSNOR (GSNOR-CMTg mice) and subjected them to endotoxic
shock. Measurements of cardiac function in vivo and ex vivo showed that GSNOR-CMTg mice had a significantly improved cardiac function after
lipopolysaccharide challenge (LPS, 50 mg/kg) compared with wild-type (WT) mice. Cardiomyocytes isolated from septic GSNOR-CMTg mice showed a corresponding improvement in contractility compared with WT cells. However, systolic Ca(2+) release was similarly depressed in both genotypes after LPS, indicating that GSNOR-CMTg cardiomyocytes have increased Ca(2+) sensitivity during
sepsis. Parameters of
inflammation were equally increased in LPS-treated hearts of both genotypes, and no compensatory changes in
NO synthase expression levels were found in GSNOR-overexpressing hearts before or after LPS challenge. GSNOR overexpression however significantly reduced total cardiac
protein S-nitrosylation during
sepsis. Taken together, our results indicate that increasing the denitrosylation capacity of cardiomyocytes protects against
sepsis-induced myocardial depression. Our findings suggest that specifically reducing
protein S-nitrosylation during
sepsis improves cardiac function by increasing cardiac myofilament sensitivity to Ca(2+).