Sphingosine kinases (SphKs) catalyze the phosphorylation of sphingosine to sphingosine-1-phosphate (S1P). Together with other sphingolipid metabolizing enzymes, SphKs regulate the balance of the lipid mediators, ceramide, sphingosine, and S1P. The ubiquitous mediator S1P regulates cellular functions such as proliferation and survival, cytoskeleton architecture and Ca(2+) homoeostasis, migration, and adhesion by activating specific high-affinity G-protein-coupled receptors or by acting intracellularly. In mammals, two isoforms of SphK have been identified. They are activated by G-protein-coupled receptors, receptor tyrosine kinases, immunoglobulin receptors, cytokines, and other stimuli. The molecular mechanisms by which SphK1 and SphK2 are specifically regulated are complex and only partially understood. Although SphK1 and SphK2 appear to have opposing roles, promoting cell growth and apoptosis, respectively, they can obviously also substitute for each other, as mice deficient in either SphK1 or SphK2 had no obvious abnormalities, whereas double-knockout animals were embryonic lethal. In this review, our understanding of structure, regulation, and functional roles of SphKs is updated and discussed with regard to their implication in pathophysiological and disease states.
Background-Hyaluronan is thought to mediate neointimal hyperplasia but also vasoprotection as an integral component of the endothelial glycocalyx. The present study addressed for the first time the effects of long-term pharmacological inhibition of hyaluronan synthesis on vascular function and atherosclerosis. Methods and Results-Four-week-old apolipoprotein E-deficient mice on a Western diet received orally an inhibitor of hyaluronan synthesis, 4-methylumbelliferone (4-MU; 10 mg/g body wt), resulting in 600 nmol/L 4-MU in plasma. As a result, aortic plaque burden was markedly increased at 25 weeks. Furthermore, acetylcholine-dependent relaxation of aortic rings was decreased and mean arterial blood pressure was increased in response to 4-MU. However, hydralazine blunted the hypertensive effect of 4-MU without inhibiting the proatherosclerotic effect. A photothrombosis model revealed a prothrombotic state that was not due to increased platelet activation or increased thrombin activation as monitored by CD62P expression and the endogenous thrombin potential. Importantly, increased recruitment of macrophages to vascular lesions was detected after 2 and 21 weeks of 4-MU treatment by immunohistochemistry, by intravital microscopy, and in a peritonitis model. As a potential underlying mechanism, severe damage of the endothelial glycocalyx after 2 and 21 weeks of treatment with 4-MU was detected by electron microscopy of the innominate artery and myocardial capillaries. Furthermore, 600 nmol/L 4-MU inhibited hyaluronan synthesis in cultured endothelial cells. Conclusions-The data suggest that systemic inhibition of hyaluronan synthesis by 4-MU interferes with the protective function of the endothelial glycocalyx, thereby facilitating leukocyte adhesion, subsequent inflammation, and progression of atherosclerosis. (Circulation. 2010;122:2313-2322.)Key Words: atherosclerosis Ⅲ inflammation Ⅲ glycocalyx Ⅲ hyaluronan H yaluronan is a ubiquitous constituent of the extracellular matrix. The synthesis is mediated through 3 hyaluronan synthase (HAS) isoforms (HAS1, HAS2, and HAS3) that assemble UDP-glucuronic acid and UDP-N-glucosamine at the plasma membrane, forming a high-molecular-weight glycosaminoglycan chain. 1 Hyaluronan is unbranched and is not further modified, in contrast to sulfated glycosaminoglycans such as heparan sulfate. 2 Extensive research on the hyaluronan system in tumor biology, 2 reproductive biology, 3 lung injury, 4 and cardiovascular pathology 5,6 has contributed to an understanding of the physiological and pathophysiological role of hyaluronan in vitro and in vivo. Clinical Perspective on p 2322In the healthy arterial vessel wall, hyaluronan is positioned at 2 strategic positions: the endothelial glycocalyx and the adventitia. However, during atherosclerosis, hyaluronan is produced by activated vascular smooth muscle cells (VSMC) in the neointima. Extensive evidence from studies on atherosclerosis and restenosis shows that hyaluronan promotes VSMC proliferation and migration and that hyaluronan accu...
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