sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models.
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.
Buys
Emmanuel S
ES
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
Cauwels
Anje
A
Raher
Michael J
MJ
Passeri
Jonathan J
JJ
Hobai
Ion
I
Cawley
Sharon M
SM
Rauwerdink
Kristen M
KM
Thibault
Helene
H
Sips
Patrick Y
PY
Thoonen
Robrecht
R
Scherrer-Crosbie
Marielle
M
Ichinose
Fumito
F
Brouckaert
Peter
P
Bloch
Kenneth D
KD
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
D004731:Endotoxins; D018160:Receptors, Cytoplasmic and Nuclear; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase; D002118:Calcium