title: sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models.
abstract: Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), suggested that cGMP generated by sGC contributed to the cardiac dysfunction and mortality associated with sepsis. We used sGC(alpha)(1)-deficient (sGC(alpha)(1)(-/-)) mice to unequivocally determine the role of sGC(alpha)(1)beta(1) in the development of cardiac dysfunction and death associated with two models of inflammatory shock: endotoxin- and TNF-induced shock. At baseline, echocardiographic assessment and invasive hemodynamic measurements of left ventricular (LV) dimensions and function did not differ between wild-type (WT) mice and sGC(alpha)(1)(-/-) mice on the C57BL/6 background (sGC(alpha)(1)(-/-B6) mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC(alpha)(1)(-/-B6) than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca(2+) handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC(alpha)(1)(-/-B6) than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC(alpha)(1)(-/-B6) compared with WT mice. Together, these findings suggest that cGMP generated by sGC(alpha)(1)beta(1) protects against cardiac dysfunction and mortality in murine inflammatory shock models.
authors.affiliation: Department of Anesthesia and Critical Care, Cardiology Division, Anesthesia Center for Critical Care Research, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA. ebuys@partners.org
authors.forename: Emmanuel S
authors.initials: ES
authors.lastname: Buys
authors.forename: Anje
authors.initials: A
authors.lastname: Cauwels
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Raher
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Passeri
authors.forename: Ion
authors.initials: I
authors.lastname: Hobai
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Cawley
authors.forename: Kristen M
authors.initials: KM
authors.lastname: Rauwerdink
authors.forename: Helene
authors.initials: H
authors.lastname: Thibault
authors.forename: Patrick Y
authors.initials: PY
authors.lastname: Sips
authors.forename: Robrecht
authors.initials: R
authors.lastname: Thoonen
authors.forename: Marielle
authors.initials: M
authors.lastname: Scherrer-Crosbie
authors.forename: Fumito
authors.initials: F
authors.lastname: Ichinose
authors.forename: Peter
authors.initials: P
authors.lastname: Brouckaert
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Bloch
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004452:Echocardiography; D004731:Endotoxins / Q000633:toxicity; D004789:Enzyme Activation / Q000502:physiology; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006162:Guanylate Cyclase / Q000235:genetics* / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009200:Myocardial Contraction / Q000502:physiology; D032383:Myocytes, Cardiac / Q000166:cytology / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D012770:Shock, Cardiogenic / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D000071756:Soluble Guanylyl Cyclase; D014409:Tumor Necrosis Factor-alpha / Q000633:toxicity; D018487:Ventricular Dysfunction, Left / Q000000981:diagnostic imaging / Q000276:immunology / Q000401:mortality; D017725:Ventricular Pressure / Q000502:physiology
chemical_list: D004731:Endotoxins; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D002118:Calcium