TITLE:

ANTI-SPHINGOLIPID ANTIBODIES MITIGATE CARDIAC REMODELING (No. 85)

DATE:

Friday, September 30th, 2005

TIME:

3:30 PM

LOCATION:

GMCS 214

SPEAKER:

Roger Sabbadini, Department of Biology, San Diego State University

ABSTRACT:

Recent literature suggests that the activation of the sphingolipid
signaling cascade is one of the earliest responses of cardiomyocytes to
redox stress caused by hypoxia and reoxygenation. Sphingomyelin, a lipid constituent of the plasma membrane, is degraded to ceramide and
sphingosine. Sphingosine is converted to Sphingosine-1-Phosphate
(S1P). Although both ceramide and sphingosine are well characterized as pro-cell death molecules, S1P has been shown to have opposite effects. S1P elicits profound effects on cell migration, proliferation and protection from cell death through activation of a series of GPCRs called S1P receptors. These effects have been seen in multiple cell types including fibroblasts and inflammatory cells. While S1P’s pro-migratory and proliferative effects on fibroblasts are well-documented in mouse embryonic fibroblasts and NIH 3T3 cells, S1P has not been studied for these roles in cardiac fibroblasts. Cardiac fibroblast migration and proliferation are, in part, responsible for post-MI scar formation and remodeling after an infarct. There is also evidence that S1P also may be a pro-inflammatory mediator that contributes to macrophage infiltration, T-cell activation (and infiltration), and cytokine release, all of which contribute to cardiac remodeling. Accordingly, we hypothesize that S1P, acting through activation of Rho kinase and Akt signaling systems, may contribute to exaggerated, maladaptive post-MI remodeling and heart failure by increasing scar formation and inflammatory responses. Our laboratory has developed a novel research tool in the form of a highly specific and sensitive mouse monoclonal antibody to S1P (anti-S1P mAb). This anti-S1P mAb acts in vitro and in vivo as a molecular sponge to selectively absorb S1P from the extracellular fluid, lowering the effective concentration of S1P and preventing ligand binding to the complement of S1P GPCRs. Preliminary studies of post-infarcted mice demonstrate that the anti-S1P mAb slows remodeling as evidenced by increased function and decreased fibrosis. We also see an apparent salvage of myocardium in the infarct zone. Thus, the anti-S1P mAb may represent an effective therapeutic against S1P-induced remodeling in the failing heart.

HOST:

Jose Castillo

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