title: Reduction of cardiomyocyte S-nitrosylation by S-nitrosoglutathione reductase protects against sepsis-induced myocardial depression.
abstract: 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+).
authors: Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129, USA. psips@partners.org
authors: Patrick Y
authors: PY
authors: Sips
authors: Tomoya
authors: T
authors: Irie
authors: Lin
authors: L
authors: Zou
authors: Shohei
authors: S
authors: Shinozaki
authors: Michihiro
authors: M
authors: Sakai
authors: Nobuyuki
authors: N
authors: Shimizu
authors: Rebecca
authors: R
authors: Nguyen
authors: Jonathan S
authors: JS
authors: Stamler
authors: Wei
authors: W
authors: Chao
authors: Masao
authors: M
authors: Kaneki
authors: Fumito
authors: F
authors: Ichinose
mesh_terms: D000426:Alcohol Dehydrogenase; D000818:Animals; D002118:Calcium / Q000378:metabolism; D009202:Cardiomyopathies / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D005980:Glutathione Reductase / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D012772:Shock, Septic / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D008070:Lipopolysaccharides; D009569:Nitric Oxide; C483598:Adh5 protein, mouse; D000426:Alcohol Dehydrogenase; D019001:Nitric Oxide Synthase; D005980:Glutathione Reductase; D002118:Calcium