sphingosine-1-phosphate and Diabetic-Angiopathies

High-density lipoproteins (HDLs) represent a family of particles characterized by the presence of apolipoprotein A-I (apoA-I) and by their ability to transport cholesterol from peripheral tissues back to the liver. In addition to this function, HDLs display pleiotropic effects including antioxidant, anti-apoptotic, anti-inflammatory, anti-thrombotic or anti-proteolytic properties that account for their protective action on endothelial cells. Vasodilatation via production of nitric oxide is also a hallmark of HDL action on endothelial cells. Endothelial cells express receptors for apoA-I and HDLs that mediate intracellular signalling and potentially participate in the internalization of these particles. In this review, we will detail the different effects of HDLs on the endothelium in normal and pathological conditions with a particular focus on the potential use of HDL therapy to restore endothelial function and integrity.

Topics: Animals; Apoptosis; Biological Transport; Blood-Brain Barrier; Diabetic Angiopathies; Drug Delivery Systems; Endothelium, Vascular; Humans; Lipoproteins, HDL; Lysophospholipids; Models, Biological; Receptors, Lipoprotein; Sphingosine; Vasculitis

Impairment of coronary flow reserve (CFR) has been generally demonstrated in diabetic patients and animals with microvascular complications but without obvious obstructive coronary atherosclerosis. There have been few studies investigating CFR in cases of relatively well-controlled therapy. The purpose of this study is to evaluate the effect of treatment with a Sphingosine-1-phosphate (S1P) receptor potent agonist, FTY720, on early diabetic rats in terms of CFR. METHODS AND RESULTS: Male Sprague-Dawley (SD) rats were divided into 3 groups: (1) streptozotocin-uninjected rats (control rats); (2) streptozotocin-injected hyperglycemic rats (diabetic group); and (3) FTY720-fed and streptozotocin-injected hyperglycemic rats. FTY720 (1.25 mg/kg per day orally) was administrated for 9 weeks in SD rats (from 6 weeks old to 15 weeks old). CFR was evaluated by (13)NH3-positron emission tomography. No obvious pathological changes of macrovascular atherosclerosis were observed in each group. Diabetic rats had impaired CFR compared with the control group (1.39±0.26 vs. 1.94±0.24, P<0.05). Treatment with FTY720 for 9 weeks attenuated the heart histological changes and improved CFR in 32% of diabetic rats (1.84±0.36 vs. 1.39±0.26, P<0.05).. In summary, long-term therapy with the Sphingosine-1-phosphate receptor agonist, FTY720, improved CFR by attenuating the heart histological changes, and it might have a beneficial effect on coronary microvascular function in diabetic rats.

Topics: Ammonia; Animals; Blood Glucose; Capillaries; Cell Adhesion Molecules; Collagen; Coronary Circulation; Coronary Disease; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Drug Evaluation, Preclinical; Fingolimod Hydrochloride; Gene Expression Regulation; Interleukin-6; Lysophospholipids; Male; Microcirculation; Myocardium; Nitrogen Radioisotopes; Positron-Emission Tomography; Propylene Glycols; Rats; Rats, Sprague-Dawley; Receptors, Lysosphingolipid; Sphingosine; Transforming Growth Factor beta

Non-obese diabetic (NOD) mice develop spontaneous type 1 diabetes. We have shown that sphingosine-1-phosphate (S1P) reduces activation of NOD diabetic endothelium via the S1P1 receptor. In the current study, we tested the hypothesis that S1P could inhibit CD4(+) T-cell activation, further reducing inflammatory events associated with diabetes.. CD4(+) T-cells were isolated from diabetic and nondiabetic NOD mouse splenocytes and treated in the absence or presence of S1P or the S1P1 receptor-specific agonist, SEW2871. Lymphocyte activation was examined using flow cytometry, cytokine bead assays, and a lymphocyte:endothelial adhesion assay.. Diabetic T-cells secreted twofold more gamma-interferon (IFN-gamma) and interleukin-17 than nondiabetic lymphocytes. Pretreatment with either S1P or SEW2871 significantly reduced cytokine secretion by approximately 50%. Flow cytometry analysis showed increased expression of CD69, a marker of lymphocyte activation, on diabetic T-cells. Both S1P and SEW2871 prevented upregulation of CD69 on CD4(+) cells. Quantitative RT-PCR showed that lymphocytes from diabetic NOD mice had 2.5-fold lower hypoxia-inducible factor (HIF)-1alpha short isoform I.1 (HIF1alphaI.1) mRNA levels than control. HIF1alphaI.1 is a negative regulator of lymphocyte activation. S1P significantly increased HIF1alpha I.1 mRNA levels in both control and diabetic groups. IFN-gamma production and surface CD69 expression was significantly increased in lymphocytes of HIF1alphaI.1-deficient mice. S1P did not reduce either CD69 or IFN-gamma expression in lymphocytes from HIF1alphaI.1-deficient mice.. S1P acts through the S1P1 receptor and HIF1alpha I.1 to negatively regulate T-cell activation, providing a potential therapeutic target for prevention of diabetes and its vascular complications.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Cytokines; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Flow Cytometry; Hypoxia-Inducible Factor 1, alpha Subunit; Lectins, C-Type; Lymphocyte Activation; Lysophospholipids; Mice; Mice, Inbred NOD; Mice, Knockout; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; Sphingosine; Spleen; T-Lymphocytes