sGCα1β1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models

Buys ES, Cauwels A, Raher MJ, Passeri JJ, Hobai I, Cawley SM, Rauwerdink KM, Thibault H, Sips PY, Thoonen R, ScherrerCrosbie M, Ichinose F, Brouckaert P, Bloch KD. sGC alpha(1)beta(1) attenuates cardiac dysfunction and mortality in murine inflammatory shock models. Am J Physiol Heart Circ Physiol 297: H654-H663, 2009. First published June 5, 2009; doi:10.1152/ajpheart.00367.2009.-Altered cGMP signaling has been implicated in myocardial depression, morbidity, and mortality associated with sepsis. Previous studies, using inhibitors of soluble guanylate cyclase (sGC), 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(-/-B6)(1) mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGC alpha(-/-B6)(1) than WT mice, as assessed using echocardiographic and hemodynamic indexes of LV function. Similarly, Ca2+ handling and cell shortening were impaired to a greater extent in cardiomyocytes isolated from sGC alpha(-/-B6)(1) than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGC alpha(-/-B6)(1) 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.