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sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models
Emmanuel S Buys1, Anje Cauwels, Michael J Raher
1Department 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
Insights
Soluble guanylate cyclase (sGC) alpha1beta1 protects against cardiac dysfunction and mortality in sepsis. Mice lacking sGC showed worsened heart problems and increased death rates during inflammatory shock.
Area of Science:
- Cardiovascular Physiology
- Sepsis Pathophysiology
- Molecular Cardiology
Background:
- Altered cyclic guanosine monophosphate (cGMP) signaling is linked to sepsis-induced myocardial depression, morbidity, and mortality.
- Prior research using soluble guanylate cyclase (sGC) inhibitors suggested sGC-generated cGMP exacerbates sepsis-related cardiac dysfunction and mortality.
Purpose of the Study:
- To definitively ascertain the role of sGC alpha1beta1 in cardiac dysfunction and mortality in endotoxin- and TNF-induced inflammatory shock models.
- To investigate the protective mechanisms of sGC alpha1beta1 in sepsis.
Main Methods:
- Utilized sGC alpha1-deficient (sGC alpha1-/-) mice and wild-type (WT) littermates on a C57BL/6 background (sGC alpha1-/-B6).
- Assessed cardiac function using echocardiography and invasive hemodynamic measurements at baseline and 14 hours post-endotoxin challenge.
- Evaluated cardiomyocyte calcium handling and cell shortening in isolated cardiomyocytes post-endotoxin challenge.
Main Results:
- No significant baseline differences in cardiac dimensions or function between sGC alpha1-/-B6 and WT mice.
- More pronounced cardiac dysfunction in sGC alpha1-/-B6 mice compared to WT mice 14 hours after endotoxin challenge.
- Impaired Ca(2+) handling and cell shortening in cardiomyocytes from sGC alpha1-/-B6 mice post-endotoxin.
- Increased morbidity and mortality in sGC alpha1-/-B6 mice during endotoxin- and TNF-induced shock compared to WT mice.
Conclusions:
- cGMP generated by sGC alpha1beta1 plays a protective role against cardiac dysfunction in murine models of inflammatory shock.
- Loss of sGC alpha1beta1 function exacerbates cardiac dysfunction and mortality in sepsis.
- Targeting sGC alpha1beta1 may offer therapeutic potential for sepsis-induced cardiovascular complications.
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.
