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Published on: January 1, 2018
Deficiency in Heat Shock Factor 1 (HSF-1) Expression Exacerbates Sepsis-induced Inflammation and Cardiac Dysfunction
Robert C Barber1, David L Maass2, D Jean White2
1University of North Texas Health Science Center, Department of Pharmacology and Neurosciences, Fort Worth, TX, USA.
Insights
Heat shock factor 1 (HSF-1) is crucial for maintaining heart function during sepsis. Its absence exacerbates inflammatory responses and impairs cardiac contractility, highlighting HSF-1
Area of Science:
- Cardiovascular Biology
- Immunology
- Molecular Biology
Background:
- Sepsis can lead to severe cardiac dysfunction.
- The role of heat shock factor 1 (HSF-1) in sepsis-induced myocardial injury is not fully understood.
- Heat shock proteins (HSPs) are known to protect cells from stress.
Purpose of the Study:
- To investigate the impact of HSF-1 absence on inflammatory cytokine production and myocardial contractility during sepsis.
- To determine if HSF-1 deficiency alters the cardiac response to sterile (LPS) and infectious (Streptococcus pneumoniae, Klebsiella pneumoniae) septic challenges.
Main Methods:
- Utilized HSF-1 knockout (hsf-/-) and wild-type littermate mice.
- Administered sterile (lipopolysaccharide; LPS) or infectious (Streptococcus pneumoniae or Klebsiella pneumoniae) septic challenges.
- Measured blood and cardiomyocyte cytokine production (TNF, IL-1β, IL-6, IL-10).
- Assessed myocardial contractility and intracellular ion responses in isolated cardiomyocytes.
Main Results:
- HSF-1 knockout mice exhibited exaggerated production of inflammatory cytokines (TNF, IL-1β, IL-6, IL-10) in blood and cardiomyocytes compared to wild-type mice.
- This enhanced myocardial inflammation in hsf-/- mice was associated with significantly decreased cardiac contraction and relaxation.
- Intracellular calcium and sodium levels in cardiomyocytes were not significantly affected by HSF-1 deficiency during sepsis, suggesting ion loading is not the primary cause of contractile defects.
Conclusions:
- HSF-1 and its downstream heat shock proteins are essential for supporting cardiac function during sepsis.
- Absence of HSF-1 leads to increased myocardial inflammation and impaired cardiac contractility in a sepsis model.
- Further research is needed to elucidate the precise mechanisms of HSF-1-mediated cardiac protection in sepsis.
Abstract:
In the present study, we investigated whether absence of heat shock factor 1 (HSF-1) and inability to increase myocardial expression of heat shock proteins alter septic responses of inflammatory cytokines and myocardial contractility. HSF-1 knockout (hsf -/-) mice and wild type litter mates underwent a sterile (lipopolysaccharide; LPS) or infectious (Streptococcus pneumoniae or Klebsiella pneumoniae) septic challenge. Production of cytokines, TNF, IL-1β, IL-6 and IL-10, in the blood and from cardiomyocytes was exaggerated in the hsf -/- mice compared to responses measured in wild type mice given an identical septic challenge. This enhanced compartmentalized myocardial inflammation was associated with significantly decreased cardiac contraction and diminished relaxation in the hsf -/- mice. However, lacking HSF-1 expression did not affect intracellular calcium and sodium responses in cardiomyocytes isolated from septic challenged mice, suggesting that ion loading was not a major or sustaining cause of the greater myocardial contractile defects in hsf -/- mice. In conclusion, our data indicated that HSF-1 and downstream heat shock proteins are essential components to support cardiac function in sepsis. Further studies are warranted to further define the precise mechanisms of HSF-1 mediated cardiac protection.
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