Abstract 1180: Protection Against Lipopolysaccharide-Induced Myocardial Dysfunction in Mice by Cardiac-Specific Expression of Soluble Fas

Abstract

The mechanisms responsible for myocardial dysfunction in the setting of sepsis remain undefined. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-specific expression of soluble Fas (sFas), a competitive inhibitor of FasL, would rescue myocardial dysfunction and inflammation in a lipopolysaccharide (LPS)-induced mouse model of sepsis. Wild-type (WT) and sFas transgenic mice were injected intraperitoneally with 10mg/kg LPS or with an equivalent volume of saline. At 18 hours after LPS administration, echocardiographic evaluation revealed a significant decrease in left ventricular fractional shortening in the WT mice, whereas it was preserved in the sFas mice (WT versus sFas, 27.5 ± 4.2% versus 43.3 ± 3.8%, P < 0.05). The increase in the transcript levels of proinflammatory cytokines, tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 resulting from LPS treatment were attenuated in the myocardium of sFas mice. sFas expression also caused a decrease in myocardial Toll-like receptor 4 (TLR-4) mRNA and protein expression. Myocardial inducible nitric oxide synthase (iNOS) expression and formation of peroxynitrite as well as apoptotic cell death were suppressed in sFas mice compared with WT mice after LPS administration. LPS-induced lung injury and increase in lung water content were also significantly reduced in sFas mice compared with WT mice (4.3 ± 0.15 versus 4.7 ± 0.88, P < 0.05). These observations indicate that neutralization of FasL by expression of sFas significantly preserved cardiac function and reduced inflammatory responses in the heart, suggesting that Fas/FasL signaling pathway is important in mediating the deleterious effects of LPS on myocardial function associated with sepsis.