Protection against lipopolysacharide-induced myocardial dysfunction in mice by cardiac-specific expression of soluble Fas

    Authors

    J. L. Niu; A. Azfer;P. E. Kolattukudy

    Comments

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    Abbreviated Journal Title

    J. Mol. Cell. Cardiol.

    Keywords

    sepsis; myocardial dysfunction; Fas/FasL signaling; lipopolysacharide; TOLL-LIKE RECEPTOR-4; NF-KAPPA-B; FAS/FAS LIGAND SYSTEM; IN-VIVO; EXPRESSION; NITRIC-OXIDE; HEART-FAILURE; LUNG INJURY; ADULT HEART; TNF-ALPHA; APOPTOSIS; Cardiac & Cardiovascular Systems; Cell Biology

    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 improve myocardial dysfunction and inflammation in a lipopolysacharide (LPS)-induced mouse model of sepsis. Wild-type (WT) and sFas transgenic mice were injected intraperitoneally with 10 mg/kg LPS or with an equivalent volume of saline. At 18 h after LPS administration, echocardiographic evaluation revealed a significant decrease in left ventricular fractional shortening in the WT mice, whereas the fractional shortening was preserved in the sFas mice. Activation of nuclear factor-kappa B (NF-kappa B) and the increase in the transcript levels of proinflammatory cytokines, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1 beta, and IL-6 resulting from LPS treatment were attenuated in the myocardium of sFas mice. sFas expression also inhibited LPS-induced upregulation of Toll-like receptor 4 (TLR-4) and inducible nitric oxide synthase (NOS), and formation of peroxyrtitrite in the myocardium. LPS-induced increase in caspase-3/7 activity and apoptotic cell death were suppressed in sFas mice compared with WT mice. LPS-induced lung injury and increase in lung water content were also significantly reduced in sFas mice. These data indicate that neutralization of FasL by expression of sFas significantly preserves cardiac function and reduces inflammatory responses in the heart, suggesting that Fas/FasL signaling pathway is important in mediating the deleterious effects of LPS on myocardial function. Published by Elsevier Inc.

    Journal Title

    Journal of Molecular and Cellular Cardiology

    Volume

    44

    Issue/Number

    1

    Publication Date

    1-1-2008

    Document Type

    Article

    Language

    English

    First Page

    160

    Last Page

    169

    WOS Identifier

    WOS:000252803700018

    ISSN

    0022-2828

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