title: Nos3 protects against systemic inflammation and myocardial dysfunction in murine polymicrobial sepsis.
abstract: NO has been implicated in the pathogenesis of septic shock. However, the role of NO synthase 3 (NOS3) during sepsis remains incompletely understood. Here, we examined the impact of NOS3 deficiency on systemic inflammation and myocardial dysfunction during peritonitis-induced polymicrobial sepsis. Severe polymicrobial sepsis was induced by colon ascendens stent peritonitis (CASP) in wild-type (WT) and NOS3-deficient (NOS3KO) mice. NOS3KO mice exhibited shorter survival time than did WT mice after CASP. NOS3 deficiency worsened systemic inflammation assessed by the expression of inflammatory cytokines in the lung, liver, and heart. Colon ascendens stent peritonitis markedly increased the number of leukocyte infiltrating the liver and heart in NOS3KO but not in WT mice. The exaggerated systemic inflammation in septic NOS3KO mice was associated with more marked myocardial dysfunction than in WT mice 22 h after CASP. The detrimental effects of NOS3 deficiency on myocardial function after CASP seem to be caused by impaired Ca handling of cardiomyocytes. The impaired Ca handling of cardiomyocytes isolated from NOS3KO mice subjected to CASP was associated with depressed mitochondrial ATP production, a determinant of the Ca cycling capacity of sarcoplasmic reticulum Ca-ATPase. The NOS3 deficiency-induced impairment of the ability of mitochondria to produce ATP after CASP was at least in part attributable to reduction in mitochondrial respiratory chain complex I activity. These observations suggest that NOS3 protects against systemic inflammation and myocardial dysfunction after peritonitis-induced polymicrobial sepsis in mice.
authors.affiliation: Department of Anesthesia, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Bougaki
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Searles
authors.forename: Kotaro
authors.initials: K
authors.lastname: Kida
authors.forename: JiaDe
authors.initials: J
authors.lastname: Yu
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001424:Bacterial Infections / Q000201:enzymology* / Q000503:physiopathology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism; D042967:Electron Transport Complex I / Q000378:metabolism; D006321:Heart / Q000503:physiopathology*; D007416:Intestinal Perforation / Q000150:complications; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008929:Mitochondria, Heart / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology*; D052250:Nitric Oxide Synthase Type III / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D010538:Peritonitis / Q000150:complications / Q000503:physiopathology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D012772:Shock, Septic / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D018746:Systemic Inflammatory Response Syndrome / Q000201:enzymology* / Q000209:etiology / Q000382:microbiology / Q000503:physiopathology
chemical_list: D016207:Cytokines; D009569:Nitric Oxide; D000255:Adenosine Triphosphate; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D042967:Electron Transport Complex I; D000252:Calcium-Transporting ATPases; D002118:Calcium