sGCα1β1attenuates 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 sGCα1-deficient (sGCα1−/−) mice to unequivocally determine the role of sGCα1β1in 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 sGCα1−/−mice on the C57BL/6 background (sGCα1−/−B6mice). At 14 h after endotoxin challenge, cardiac dysfunction was more pronounced in sGCα1−/−B6than 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 sGCα1−/−B6than WT mice after endotoxin challenge. Importantly, morbidity and mortality associated with inflammatory shock induced by endotoxin or TNF were increased in sGCα1−/−B6compared with WT mice. Together, these findings suggest that cGMP generated by sGCα1β1protects against cardiac dysfunction and mortality in murine inflammatory shock models.