sGC(alpha)1(beta)1 attenuates cardiac dysfunction and mortality in murine inflammatory shock models

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.