title: Cardiomyocyte-specific overexpression of nitric oxide synthase 3 prevents myocardial dysfunction in murine models of septic shock.
abstract: Myocardial dysfunction contributes to the high mortality of patients with endotoxemia. Although nitric oxide (NO) has been implicated in the pathogenesis of septic cardiovascular dysfunction, the role of myocardial NO synthase 3 (NOS3) remains incompletely defined. Here we show that mice with cardiomyocyte-specific NOS3 overexpression (NOS3TG) are protected from myocardial dysfunction and death associated with endotoxemia. Endotoxin induced more marked impairment of Ca(2+) transients and cellular contraction in wild-type than in NOS3TG cardiomyocytes, in part, because of greater total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+) in the latter during endotoxemia. Endotoxin increased reactive oxygen species production in wild-type but not NOS3TG hearts, in part, because of increased xanthine oxidase activity. Inhibition of NOS by N(G)-nitro-l-arginine-methyl ester restored the ability of endotoxin to increase reactive oxygen species production and xanthine oxidase activity in NOS3TG hearts to the levels measured in endotoxin-challenged wild-type hearts. Allopurinol, a xanthine oxidase inhibitor, attenuated endotoxin-induced reactive oxygen species accumulation and myocardial dysfunction in wild-type mice. The protective effects of cardiomyocyte NOS3 on myocardial function and survival were further confirmed in a murine model of polymicrobial sepsis. These results suggest that increased myocardial NO levels attenuate endotoxin-induced reactive oxygen species production and increase total sarcoplasmic reticulum Ca(2+) load and myofilament sensitivity to Ca(2+), thereby reducing myocardial dysfunction and mortality in murine models of septic shock.
authors.affiliation: Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114, USA. fichinose@partners.org
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Tomas G
authors.initials: TG
authors.lastname: Neilan
authors.forename: Elissa M
authors.initials: EM
authors.lastname: Furutani
authors.forename: John G
authors.initials: JG
authors.lastname: Morgan
authors.forename: Davinder S
authors.initials: DS
authors.lastname: Jassal
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Graveline
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Searles
authors.forename: Chee C
authors.initials: CC
authors.lastname: Lim
authors.forename: Masao
authors.initials: M
authors.lastname: Kaneki
authors.forename: Michael H
authors.initials: MH
authors.lastname: Picard
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: Stefan
authors.initials: S
authors.lastname: Janssens
authors.forename: Ronglih
authors.initials: R
authors.lastname: Liao
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
mesh_terms: D008841:Actin Cytoskeleton; D000493:Allopurinol / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002316:Cardiotonic Agents / Q000378:metabolism*; D019446:Endotoxemia / Q000201:enzymology / Q000503:physiopathology; D004731:Endotoxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006331:Heart Diseases / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology; D032383:Myocytes, Cardiac / Q000201:enzymology*; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D012772:Shock, Septic / Q000139:chemically induced / Q000401:mortality / Q000503:physiopathology*; D014969:Xanthine Oxidase / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D000493:Allopurinol; D002118:Calcium; D002135:Calcium-Binding Proteins; D002316:Cardiotonic Agents; D004731:Endotoxins; D004791:Enzyme Inhibitors; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D017382:Reactive Oxygen Species; D014969:Xanthine Oxidase; D000099211:Phospholamban