دانلود رایگان مقاله مهار چسبندگی ماکروفاژ توسط SPC برای عروق سلولهای عضله صاف

abstract

Inflammation in de-endothelialised arteries contributes to the development of cardiovascular diseases. The process that initiates this inflammatory response is the adhesion of monocytes/macrophages to exposed vascular smooth muscle cells, typically stimulated by cytokines such as tumour necrosis factor-a (TNF). The aim of this study was to determine the effect of the sphingolipid sphingosylphosphorylcholine (SPC) on the interaction of monocytes/macrophages with vascular smooth muscle cells. Rat aortic smooth muscle cells and rat bone marrow-derived macrophages were co-cultured using an in vitro assay following incubation with sphingolipids to assess inter-cellular adhesion. We reveal that SPC inhibits the TNF-induced adhesion of macrophages to smooth muscle cells. This anti-adhesive effect was the result of SPC-induced changes to the smooth muscle cells (but not the macrophages) and was mediated, at least partly, via the sphingosine 1-phosphate receptor subtype 2. Lipid raft domains were also required. Although SPC did not alter expression or membrane distribution of the adhesion proteins intercellular adhesion molecule-1 and vascular cellular adhesion protein-1 in smooth muscle cells, SPC preincubation inhibited the TNF-induced increase in inducible nitric oxide synthase (NOS2) resulting in a subsequent decrease in nitric oxide production. Inhibiting NOS2 activation in smooth muscle cells led to a decrease in the adhesion of macrophages to smooth muscle cells. This study has therefore delineated a novel pathway which can inhibit the interaction between macrophages and vascular smooth muscle cells via SPC-induced repression of NOS2 expression. This mechanism could represent a potential drug target in vascular disease.

4. Discussion

The interaction of monocytes/macrophages with vascular SMC in vivo is a central component of the pathogenesis of cardiovascular disease [10]. In this study, the effect of the naturally-occurring sphingolipid SPC on macrophage adhesion to vascular SMC was investigated. SPC significantly decreased TNF-induced adhesion of BMDM to vascular SMC in an in vitro co-culture model. This antiadhesive action of SPC occurred via an effect directly on SMC, but not BMDM. The SPC-induced signal transduction is at least partly receptor-dependent (via activation of the S1P2 receptor). The intracellular mechanisms of this effect were not due to changes in the expression or membrane distribution of the adhesion proteins ICAM-1 and VCAM-1, however they were dependent on an inhibition of TNF-induced NOS2 expression via the S1P2 receptor. In addition, a distinct lipid raft-dependent mechanism is also involved (independent of S1P receptors). This novel effect of SPC would be expected to decrease localised vascular inflammation and may have important implications for cardiovascular disease.