Ryudocan (syndecan-4) deficiency increases susceptibility to LPS-induced shock in mice

Abstract number: OC265

Kojima^* T., Ishiguro^* K., Takagi^* A., Iwase^* M., Adachi^* T., Hayashi^* M., Takeshita^* K., Yamamoto^* K., Matsushita^* T., Saito† H.

†Nagoya National University, Japan ^*Nagoya University, Japan;

Ryudocan is a transmembrane heparan sulfate proteoglycan, originally cloned as an anticoagulant molecule from the rat microvascular endothelial cells, and now also called syndecan-4. We have made syndecan-4-deficient mice by the gene targeting and found that the deficiency impairs focal adhesion formation under restricted conditions and fetal vessels in the placental labyrinth, and increases susceptibility to k-carrageenan-induced obstructive nephropathy. In this study, we describe an unexpected finding that syndecan-4 is involved in a mechanism avoiding endotoxin shock. Following intraperitoneal injection of lipopolysaccharide (LPS: 10 mg kg^-1), syndecan-4-deficient mice exhibited high mortality compared to wild-type controls (84.4% vs. 21.9%; P < 0.01). Severe endotoxin shock was observed in the deficient mice: systolic blood pressure and left ventricular fractional shortening were lower in the deficient mice than in the wild-type controls 9 h after LPS injection. Although histological examinations revealed no apparent differences between two groups, the plasma level of interleukin (IL)-1b was higher in the deficient mice than in the wild-type controls 9 h after LPS injection. Consistent with the regulatory roles of syndecan-4, its expression in monocytes and endothelial cells of microvasculature increased in the wild-type mice after LPS administration. Although IL-1b was produced to the same extent by macrophages from syndecan-4-deficient and wild-type mice after LPS stimulation, inhibition of its production by transforming growth factor (TGF)-b 1 was impaired in the syndecan-4-deficient macrophages. Syndecan-4 bound to TGF-b 1 via its heparan-sulfate chains and its deficiency reduced the amount of TGF-b 1 bound onto macrophages. These results indicate that syndecan-4 could be involved in prevention of endotoxin shock, at least partly through the inhibitory action of TGF-b 1 on IL-1b production. Syndecan-4 is a member of the syndecan family, which consists of 4 closely related molecules. The plasma membrane also contains the glypican family, which are 6 heparan sulfate proteoglycans linked to the membrane via a glycosylphosphatidylinositol. Therefore, it was remarkable that deficiency of only one heparan sulfate proteoglycan (syndecan-4) significantly alters susceptibility to endotoxin shock. This finding will be important in investigating genetic factors affecting susceptibility to septic shock in patients.