title: Lysozyme binding to endocardial endothelium mediates myocardial depression by the nitric oxide guanosine 3',5' monophosphate pathway in sepsis.
abstract: Inflammatory mediators have been implicated as a cause of reversible myocardial depression in septic shock. We previously reported that the release of lysozyme-c (Lmz-S) from leukocytes from the spleen or other organs contributes to myocardial dysfunction in Escherichia coli septic shock in dogs by binding to a cardiac membrane glycoprotein. However, the mechanism by which Lzm-S causes this depression has not been elucidated. In the present study, we tested the hypothesis that the binding of Lzm-S to a membrane glycoprotein causes myocardial depression by the formation of nitric oxide (NO). NO generation then activates soluble guanylyl cyclase and increases cyclic guanosine monophosphate (cGMP), which in turn triggers contractile impairment via activation of cGMP-dependent protein kinase (PKG). We examined these possibilities in a right ventricular trabecular preparation in which isometric contraction was used to measure cardiac contractility. We found that Lzm-S's depressant effect could be prevented by the non-specific NO synthase (NOS) inhibitor N(G)-monomethyl-l-arginine (l-NMMA). A guanylyl cyclase inhibitor (ODQ) and a PKG inhibitor (Rp-8-Br-cGMP) also attenuated Lzm-S's depressant effect as did chemical denudation of the endocardial endothelium (EE) with Triton X-100 (0.5%). In EE tissue, we further showed that Lzm-S caused NO release with use of 4,5 diaminofluorescein, a fluorescent dye that binds to NO. The present study shows that the binding of Lzm-S to EE generates NO, and that NO then activates the myocardial guanosine 3',5' monophosphate pathway leading to cardiac depression in sepsis.
authors.affiliation: Department of Medicine, Health Sciences Center, University of Manitoba, 700 William Avenue, Winnipeg, Mannitoba, Canada. minksn@cc.umanitoba.ca
authors.forename: Steven N
authors.initials: SN
authors.lastname: Mink
authors.forename: Ratna
authors.initials: R
authors.lastname: Bose
authors.forename: Diane E
authors.initials: DE
authors.lastname: Roberts
authors.forename: Hans
authors.initials: H
authors.lastname: Jacobs
authors.forename: Krika
authors.initials: K
authors.lastname: Duke
authors.forename: Deepak
authors.initials: D
authors.lastname: Bose
authors.forename: Zhao-Qin
authors.initials: ZQ
authors.lastname: Cheng
authors.forename: R Bruce
authors.initials: RB
authors.lastname: Light
mesh_terms: D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D004285:Dogs; D004699:Endocardium / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D004727:Endothelium / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D009113:Muramidase / Q000378:metabolism / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D018805:Sepsis / Q000378:metabolism* / Q000503:physiopathology*; D019323:omega-N-Methylarginine / Q000494:pharmacology
chemical_list: C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D010069:Oxadiazoles; D011810:Quinoxalines; D019323:omega-N-Methylarginine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D009113:Muramidase; D006152:Cyclic GMP