Abstract 15878: Decreased Vascular Nitric Oxide Production Due to S100A1 Deficiency Preserves Cardiovascular Function and Survival in a Murine Model of Polymycrobial Sepsis
Introduction: Sepsis-induced myocardial depression is a key component contributing to septic shock. The mechanisms responsible for myocardial dysfunction in sepsis remain undefined. S100A1 a member of the EF-hand calcium binding protein family is a key mediator of contractile performance, cell survival and metabolism through its actions on intracellular calcium cycling. S100A1 is decreased in failing hearts and restoring S100A1 levels reverses cardiac dysfunction.
Hypothesis: To assess a possible role of S100A1 in a murine model of sepsis.
Methods: We examined the pattern and functional impact of S100A1 expression in the heart and vasculature of 10-12 week old wild-type (WT) and S100A1 knockout mice (SKO) following 48 hrs of induction of polymycrobial sepsis by cecal ligation and perforation (CLP).
Results: Compared to sham (n=6), CLP in WT (n=26) produced bacterial peritonitis with deleterious cardiac dysfunction (30% decrease in left ventricular systolic pressure (LVSP), 36.5% decrease in dp/dtmax), 22.9% decrease in ejection fraction (EF)), a 55% decrease in LV, abdominal and thoracic aortic S100A1 mRNA and protein and 60% mortality. In comparison, and unexpectedly, septic SKO (n=15) had mild cardiac dysfunction (12% decrease in LVSP, 18.5% decrease in dp/dtmax and a 6% decrease in EF) and 0 mortality. LV end diastolic pressure remained unchanged in septic WT and SKO mice. Whereas cardiac levels of nitric oxide synthase (NOS)2 mRNA and NO as quantified by Nitrate/Nitrite production were similar in septic WT and SKO, abdominal and thoracic aortic levels were increased 3-4 fold in WT compared to SKO. Confirming a prominent role of NO in cardiovascular dysfunction of sepsis, compared to sham (n=10), NOS2 KO mice in response to CLP (n=10) developed mild cardiac dysfunction (10% decrease in LVSP, 15% decrease in dp/dtmax, 16.5% decrease in EF) and 10% mortality similar to septic SKO. Interestingly, following CLP, cardiovascular S100A1 levels in NOS2 KO were similar to septic WT.
Conclusions: Our data suggests a decrease in NO production due to S100A1 deficiency in the vasculature may be beneficial in the preservation of cardiovascular function and survival following sepsis. Our data supports a role for NO as a potential therapeutic target in sepsis.
Author Disclosures: J. Tsoporis: None. J. Desjardins: None. S. Izhar: None. T.G. Parker: None.
- © 2016 by American Heart Association, Inc.