sGC{alpha}1{beta}1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models

doi:10.1152/ajpheart.00367.2009

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sGC ${alpha}$ ₁β₁ attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Emmanuel S. Buys,¹^,2^,* Anje Cauwels,³^,4^,* Michael J. Raher,¹^,2 Jonathan J. Passeri,⁵ Ion Hobai,¹ Sharon M. Cawley,² Kristen M. Rauwerdink,¹ Helene Thibault,⁵ Patrick Y. Sips,¹ Robrecht Thoonen,³^,4 Marielle Scherrer-Crosbie,²^,5 Fumito Ichinose,¹ Peter Brouckaert,³^,4 and Kenneth D. Bloch¹^,2

¹Anesthesia Center for Critical Care Research, Department of Anesthesia and Critical Care, and ⁵Cardiac Ultrasound Laboratory, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston; ²Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts; ³Department of Medical Molecular Biology, Flanders Institute for Biotechnology and ⁴Department of Molecular Biology, Ghent University, Ghent, Belgium

Submitted 17 April 2009 ; accepted in final form 30 May 2009

Altered cGMP signaling has been implicated in myocardial depression,morbidity, and mortality associated with sepsis. Previous studies,using inhibitors of soluble guanylate cyclase (sGC), suggestedthat cGMP generated by sGC contributed to the cardiac dysfunctionand mortality associated with sepsis. We used sGC ${alpha}$ ₁-deficient(sGC ${alpha}$ ₁^–/–) mice to unequivocally determine the roleof sGC ${alpha}$ ₁β₁ in the development of cardiac dysfunction anddeath associated with two models of inflammatory shock: endotoxin-and TNF-induced shock. At baseline, echocardiographic assessmentand 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^–/–B6than WT mice, as assessed using echocardiographic and hemodynamicindexes of LV function. Similarly, Ca²⁺ handling and cell shorteningwere impaired to a greater extent in cardiomyocytes isolatedfrom sGC ${alpha}$ ₁^–/–B6 than WT mice after endotoxin challenge.Importantly, morbidity and mortality associated with inflammatoryshock induced by endotoxin or TNF were increased in sGC ${alpha}$ ₁^–/–B6compared with WT mice. Together, these findings suggest thatcGMP generated by sGC ${alpha}$ ₁β₁ protects against cardiac dysfunctionand mortality in murine inflammatory shock models.

soluble guanylate cyclase; left ventricular function; sepsis; mice; nitric oxide

Address for reprint requests and other correspondence: E. S. Buys, Anesthesia Center for Critical Care Research, Dept. of Anesthesia and Critical Care, Massachusetts General Hospital, 50 Blossom St., Thier 505, Boston, MA 02114 (e-mail: ebuys{at}partners.org)

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sGC1β1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models

sGC ${alpha}$ ₁β₁ attenuates cardiac dysfunction and mortality in murine inflammatory shock models