sphingosine-1-phosphate and Constriction--Pathologic

To determine the changes of serum copeptin and sphingosine 1-phosphate (S1P) in patients with restenosis after stent implantation of symptomatic intracranial artery stenosis.. An observational study.. Changyi people's Hospital, China, from February 2016 to November 2019.. A total of 76 patients with symptomatic intracranial artery stenosis and stent implantation were divided into the restenosis group (n = 16) and the non-restenosis group (n=60) according to the intracranial artery restenosis occurred after the follow-up of 1 year. Levels of serum copeptin and S1P were compared between the groups.. There were significant differences in diabetes mellitus and hypertension between the two groups (p<0.001 and p = 0.017, respectively). There were no significant differences in serum copeptin and S1P levels between the two groups before and 3 days after the operation (p = 0.927, 0.792, 0.776, and 0.906, respectively). Postoperative follow-up of one year, levels of serum copeptin in the restenosis group were higher than those in the non-restenosis group (p<0.001), and levels of serum S1P in the restenosis group were lower than those in the non-restenosis group (p = 0.003).. High serum copeptin level, low serum S1P level, hypertension, and diabetes mellitus are independent risk factors promoting restenosis after stent implantation in patients with symptomatic intracranial artery stenosis.. Copeptin, Sphingosine 1-phosphate (S1P), Symptomatic intracranial artery stenosis, Stent implantation, Restenosis.

Topics: Arteries; Constriction, Pathologic; Diabetes Mellitus; Follow-Up Studies; Glycopeptides; Humans; Hypertension; Lysophospholipids; Sphingosine; Stents

Inhibition of histone deacetylase-2 (HDAC2), which is a prohypertrophic factor in the heart, can functionally attenuate cardiac hypertrophy. The present study aimed to investigate whether sphingosine‑1‑phosphate (S1P), which has recently been reported to suppress HDAC2 activity, could ameliorate the cardiac hypertrophic response and improve cardiac function in mice with transverse aortic constriction (TAC), as well as to determine the underlying mechanisms. Briefly, 8‑week‑old male C57BL/6 mice were randomly divided into sham, TAC and TAC + S1P groups; the results indicated that S1P treatment attenuated TAC‑induced cardiac dysfunction. In addition, heart size and the expression levels of fetal cardiac genes were reduced in the TAC + S1P group compared with in the TAC group. Furthermore, in cultured H9c2 cells exposed to phenylephrine, S1P was revealed to decrease cardiomyocyte size and the exaggerated expression of fetal cardiac genes. The present study also demonstrated that S1P had no effect on HDAC2 expression, but it did suppress its activity and increase acetylation of histone H3 in vivo and in vitro. Krüppel‑like factor 4 (KLF4) is an antihypertrophic transcriptional regulator, which mediates HDAC inhibitor‑induced prevention of cardiac hypertrophy; in the present study, KLF4 was upregulated by S1P. Finally, the results indicated that S1P receptor 2 (S1PR2) may be involved in the antihypertrophic effects, whereas the suppressive effects of S1P on HDAC2 activity were independent of S1PR2. In conclusion, the present study demonstrated that S1P treatment may ameliorate the cardiac hypertrophic response, which may be partly mediated by the suppression of HDAC2 activity and the upregulation of KLF4; it was suggested that S1PR2 may also be involved. Therefore, S1P may be considered a potential therapy for the treatment of heart diseases caused by cardiac hypertrophy.

Topics: Animals; Aorta; Cardiomegaly; Cells, Cultured; Constriction, Pathologic; Electrocardiography; Hemodynamics; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Kruppel-Like Factor 4; Kruppel-Like Transcription Factors; Lysophospholipids; Male; Mice, Inbred C57BL; Models, Biological; Phenylephrine; Rats; Receptors, Lysosphingolipid; RNA, Small Interfering; Sphingosine; Up-Regulation

Although sphingosine 1-phosphate (S1P), a bioactive lipid derived from activated platelets, has a variety of physiologic effects on vessels, no reports have described the effect of S1P on the retinal circulation. We examined the effect and underlying mechanism of the vasomotor action of S1P on porcine retinal arterioles. The porcine retinal arterioles were isolated, cannulated, and pressurized without flow for in vitro study. S1P-induced diameter changes were recorded using videomicroscopic techniques. S1P elicited concentration-dependent (1 nM-10 μM) vasoconstriction of the retinal arterioles that was abolished by the S1P receptor 2 (S1PR2) antagonist JTE-013. S1P-induced vasoconstriction was abolished by the Rho kinase (ROCK) inhibitor H-1152 and was inhibited partly by the protein kinase C (PKC) inhibitor Gö-6983. The inhibition of phospholipase C by U73122 and L-type voltage-operated calcium channels (L-VOCCs) by nifedipine inhibited S1P-induced vasoconstriction; a combination of both inhibitors abolished S1P-induced vasoconstriction. Furthermore, inhibition of myosin light chain kinase (MLCK) by ML-9 significantly blocked S1P-induced vasoconstriction; further coadministration of ML-9 with H-1152 or Gö-6983 abolished S1P-induced vasoconstriction. The current data suggest that S1P elicits vasoconstriction of the retinal arterioles via S1PR2 in vascular smooth muscle cells and this vasoconstriction may be mediated by the Ca2+ -sensitive pathway via activation of PKC leading to activation of ROCK and the Ca2+ -dependent pathway via activation of L-VOCCs resulting in activation of MLCK.

Topics: Actins; Animals; Arterioles; Calcium; Calcium Channels, L-Type; Constriction, Pathologic; Dose-Response Relationship, Drug; Endothelium, Vascular; Female; Fluorescent Antibody Technique, Indirect; Indoles; Lysophospholipids; Male; Maleimides; Muscle, Smooth, Vascular; Myosin Light Chains; Nitric Oxide Synthase Type III; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptors, Lysosphingolipid; Retinal Artery; rho-Associated Kinases; Sphingosine; Swine

We have recently demonstrated a reduction in HDL-bound sphingosine 1-phosphate (S1P) in patients with stable coronary artery disease (CAD). In the current study, we tested whether HDL-associated S1P is predictive for the degree of coronary stenosis, restenosis and overall CAD severity on follow up in patients undergoing elective percutaneous coronary intervention (PCI).. Coronary angiography of patients with CAD (n=59) undergoing elective PCI and presenting for a follow up after 6 months (n=48) was graded for disease severity defined clinically as 1- or multi-vessel disease. Target lesion stenosis was quantified by quantitative coronary angiography (QCA). S1P in plasma and isolated HDL were measured by mass spectrometry in the initial samples and in 32 available follow up samples.. HDL-bound S1P levels remained stable over time and correlated closely at first visit and follow up. While not associated with the extent of target lesion stenosis or restenosis, HDL-bound S1P correlated negatively with the overall severity of CAD and discriminated 1-vessel-disease from multi-vessel disease. Furthermore, low HDL-bound S1P was predictive for CAD extent.. In stable CAD, HDL-bound S1P does not predict the degree of stenosis or restenosis of the target lesion but constitutes a marker of clinically defined disease burden.

Topics: Aged; Area Under Curve; Constriction, Pathologic; Coronary Angiography; Coronary Artery Disease; Female; Humans; Lipoproteins, HDL; Lysophospholipids; Male; Mass Spectrometry; Middle Aged; Percutaneous Coronary Intervention; Protein Binding; ROC Curve; Severity of Illness Index; Sphingosine

About a quarter of peripheral vein grafts fail due in part to intimal hyperplasia. The proliferative capacity and response to growth inhibitors of medial smooth muscle cells and adventitial fibroblasts in vitro were studied to test the hypothesis that intrinsic differences in cells of vein grafts are associated with graft failure.. Cells were grown from explants of the medial and adventitial layers of samples of vein grafts obtained at the time of implantation. Vein graft patency and function were monitored over the first 12 months using ankle pressures and Duplex ultrasound to determine vein graft status. Cells were obtained from veins from 11 patients whose grafts remained patent (non-stenotic) and from seven patients whose grafts developed stenosis. Smooth muscle cells (SMCs) derived from media and fibroblasts derived from adventitia were growth arrested in serum-free medium and then stimulated with 1 muM sphingosine-1-phosphate (S1P), 10 nM thrombin, 10 ng/ml epidermal growth factor (EGF), 10 ng/ml platelet-derived growth factor-BB (PDGF-BB), PDGF-BB plus S1P, or PDGF-BB plus thrombin for determination of incorporation of [(3)H]-thymidine into DNA. Cells receiving PDGF-BB or thrombin were also treated with or without 100 microg/ml heparin, which is a growth inhibitor. Cells receiving thrombin were also treated with or without 150 nM AG1478, an EGF receptor kinase inhibitor.. SMCs and fibroblasts from veins of patients that developed stenosis responded more to the growth factors, such as PDGF-BB alone or in combination with thrombin or S1P, than cells from veins of patients that remained patent (P = .012). In addition, while PDGF-BB-mediated proliferation of fibroblasts from grafts that remained patent was inhibited by heparin (P < .03), PDGF-BB-mediated proliferation of fibroblasts from veins that developed stenosis was not (P > .5).. Inherent differences in the proliferative response of vein graft cells to PDGF-BB and heparin may explain, in part, the variability among patients regarding long term patency of vein grafts.

Topics: Aged; Ankle; Becaplermin; Blood Pressure; Cell Proliferation; Cells, Cultured; Constriction, Pathologic; DNA Replication; Epidermal Growth Factor; Female; Fibroblasts; Graft Occlusion, Vascular; Heparin; Humans; Hyperplasia; Lower Extremity; Lysophospholipids; Male; Middle Aged; Myocytes, Smooth Muscle; Peripheral Vascular Diseases; Platelet-Derived Growth Factor; Protein Kinase Inhibitors; Proto-Oncogene Proteins c-sis; Quinazolines; Saphenous Vein; Sphingosine; Thrombin; Time Factors; Tyrphostins; Ultrasonography, Doppler, Duplex; Vascular Patency