Deficiency in Heat Shock Factor 1 (HSF-1) Expression Exacerbates Sepsis-induced Inflammation and Cardiac Dysfunction

Severe sepsis is a leading cause of death in intensive care units [1,2]. Despite improvements in antibiotic therapies and critical care techniques [3], approximately 215,000 Americans still die from sepsis each year [4]. Present treatment for sepsis continues to be supportive care and source control, such as using intravenous fluids and oxygen, and/or antibiotics and procedural interventions [3]. Most attempts at molecule-based treatments have failed clinically [5,6]. To date, our understanding of sepsis pathogenesis and therapeutic options are still limited. Therefore, investigation of the pathological mechanisms and exploration of new therapeutic interventions are clearly needed to advance the treatment of this devastating condition. Cardiac dysfunction is a vital component of multi-organ failure during severe sepsis [7-9]. Increased cardiac expression of heat shock protein 70 (HSP70) has been described after ischemic injury [10], hypoxia [11] and major burn [12]. A cardioprotective role has been suggested for HSP70, which is believed to function as a molecular chaperone that inhibits apoptosis and necrosis secondary to inhibitory effects on caspases [13]. HSPs may also provide cardioprotection through their ability to interact with cytoskeletal proteins by stabilizing cytoskeletal structures and increasing resistance to stress [14,15]. HSP70 expression after injury or stress is regulated by heat shock transcription factor-1 (HSF-1) [16]. Stress promotes HSF1 conversion from a monomeric form in the cytoplasm to a trimerized phosphorylated form, which then translocates to the nucleus to promote the transcription of heat shock proteins [17]. In the heart, HSF1 deficiency reduces cardiac expression of Hsp25, alphaB-crystallin and Hsp70 [16]. The role of HSF-1/ HSP70 in inflammation has been emphasized by the finding that HSF-1 deficient mice exhibit chronically elevated systemic TNF levels as well as increased susceptibility to LPS challenge [18]. In this study, using HSF-1 knockout (hsf-/-) mice as a model, we examined the role of HSF-1 in inflammation and cardiac function in response to septic challenge by lipopolysaccharide (LPS), grampositive bacteria Streptococcus pneumoniae (S. pneumoniae), or gram-negative bacteria Klebsiella pneumoniae (K. pneumoniae).