1-磷酸鞘氨醇及其受体与动脉粥样硬化研究进展

<正>动脉粥样硬化(AS)的发病机制尚未完全清楚,研究表明,AS是一种慢性免疫-炎症性疾病,是血管壁对各种损伤的一种异常反应~(〔1〕)。大量流行病学数据表明高密度脂蛋白(HDL)具有抗AS作用,近些年发现与HDL结合的1-磷酸鞘氨醇(S1P)在抗AS中发挥着重要作用~(〔1〕)。S1P影响着不同细胞的增殖、迁移、黏附、炎症等,在心血管、神经、免疫、呼吸等多个系统有着重要的作用,S1PR激动剂FTY720已经应用于临床治疗多发     

鞘氨醇-1-磷酸在支气管哮喘中作用的研究进展

鞘类脂质是一类广泛存在于各种真核细胞膜上的分子类物质。鞘脂类最初被认为是细胞膜的结构组成部分,随着研究的深入发现此类物质同时也是重要的信号分子。鞘氨醇-1-磷酸（sphingosine-1-phosphate,S1P）是鞘脂类的代谢产物,在细胞的变异、增殖、凋亡以及血管生成的过程中是重要的生物活性信号。S1P在支气管哮喘的发病机制中扮演了重要角色。近期研究表明在肥大细胞中鞘氨醇激酶的激活通过FceRI信号通路使鞘氨醇转变为SIP,参与诱导了气道平滑肌的收缩和气道重塑。这些新发现的信号途径为支气管哮喘患者提供了潜在的治疗靶点。     

鞘氨醇-1-磷酸在支气管哮喘中作用的研究进展

鞘类脂质是一类广泛存在于各种真核细胞膜上的分子类物质.鞘脂类最初被认为是细胞膜的结构组成部分,随着研究的深入发现此类物质同时也是重要的信号分子.鞘氨醇-1-磷酸(sphingosine-1-phosphate,S1P)是鞘脂类的代谢产物,在细胞的变异、增殖、凋亡以及血管生成的过程中是重要的生物活性信号.S1P在支气管哮喘的发病机制中扮演了重要角色.近期研究表明在肥大细胞中鞘氨醇激酶的激活通过FcεRI信号通路使鞘氨醇转变为S1P,参与诱导了气道平滑肌的收缩和气道重塑.这些新发现的信号途径为支气管哮喘患者提供了潜在的治疗靶点.     

抑制1-磷酸鞘氨醇裂解酶活性加重缺血性心力衰竭

目的:观察1-磷酸鞘氨醇(S1P)裂解酶(SPL)在小鼠缺血性心衰(HF)模型中的作用。方法:将60只成年雄性C57/BL6J小鼠随机分为以下4组:假手术(Sham)组、心肌梗死(MI)组、假手术+THI(Sham+THI)组[THI是SPL的抑制剂]及MI+THI组,每组15只(n=15),将25 mg/L THI溶于饮水中,于手术24 h后连续饲喂2周。MI4周后,采用ELISA试剂盒测定心肌中S1P的含量。根据心脏质量/体质量(HW/BW)评价心肌肥厚。用小动物心脏超声评估小鼠心脏结构和功能,经Masson三色染剂染色法观察心脏纤维化。用Western blot检测转化生长因子-β(TGF-β)蛋白的表达。实时PCR检测Ⅰ、Ⅲ型胶原、心房钠尿肽(ANP)、脑钠尿肽(BNP)和平滑肌肌动蛋白-α(α-SMA)mRNA的水平。结果:与MI组相比,MI+THI组小鼠心肌组织中S1P的含量增加(P0.01);左心室射血分数(LVEF)降低(P0.01),左心室收缩末期内径(LVESD)和舒张末期内径(LVEDD)均增加(均P0.05),HW/BW增加(P0.01),心脏纤维化加重;TGF-β蛋白的表达增加(P0.01);Ⅰ、Ⅲ型胶原、ANP、BNP和α-SMA mRNA的水平均显著增加(均P0.01)。与Sham组相比,Sham+THI组小鼠上述指标无显著差异。结论:抑制SPL的活性可能增加梗死后心肌病理性S1P信号的激活,加重MI后的心脏重构和HF。     

1-磷酸鞘氨醇对心肌细胞内游离钙离子浓度的影响

目的研究1-磷酸鞘氨醇（sphingosine-1-phosphate,SIP）对体外培养的乳鼠心肌细胞内游离钙离子浓度的作用。方法应用钙离子荧光指示剂Fluo-3AM负载原代培养的大鼠心肌细胞,通过激光共聚焦扫描显微镜上机检测,记录其荧光强度变化。结果@SIP能降低[Ca2＋]i平均荧光强度值,对照组由（743．15±34．78）nmol／L降至（446．89±55．36）nmol／L（P〈O．01,n=7）;而S1P（1．1μmol／L）＋苏拉明（Suramin）（200μmol／L）组[ca2＋]i平均荧光强度值由（778．39±42．15）nmol／L降至（759．41±38．17）nmol／L,差异无统计学意义（P〉O．05,n=7）。结论S1P可降低乳鼠心肌细胞内游离钙离子浓度,这种作用可能通过其特异性的G蛋白耦联S1P受体介导产生。     

1-磷酸鞘氨醇及其受体对血管炎症的影响

<正>心血管疾病是一种慢性炎症性疾病,血管壁炎症反应贯穿心血管疾病的全过程。1-磷酸鞘氨醇(S1P)与靶细胞表面的1-S1P受体(S1PR)结合,激活不同的细胞内信号途径而影响细胞的增殖、凋亡、迁移、分化、血管生成和创伤愈合等,本文就S1P及其受体对血管炎症的影响进行综述。1 S1P概述1.1 S1P的生成、代谢及转运S1P是磷脂代谢的重要代谢产物,其前体物质鞘氨醇主要由软脂酰乙酰辅酶(Co)A及丝氨酸     

1-磷酸神经鞘氨醇对心血管系统的作用

1-磷酸神经鞘氨醇(S1P)是一种有生物活性的脂质代谢产物,具有调节细胞增殖、再生、迁移及细胞内钙离子移动、黏附分子表达和激活单核细胞黏附内皮细胞等生物功效,在血管生理性再生及动脉粥样硬化斑块发生发展中起着重要作用。本文综述S1P在心血管系统中的生理病理作用。     

1-磷酸鞘氨醇对人胚胎肺纤维细胞增殖作用的影响

目的 研究1-磷酸鞘氨醇(S1P)在肺组织修复过程中的作用及其机制.方法 用1、10 μM S1P及其受体激动剂SEW2871处理人胚胎肺纤维细胞,分别将10 μM细胞外信号调节激酶(ERK)拮抗剂PD98059、磷脂酰肌醇3-激酶/蛋白激酶B(PI3K/Akt)拮抗剂LY294002与1 μM S1P共同处理人胚胎肺纤维细胞48 h,观察对细胞增殖的影响;采用Western blot法研究信号传导通路.结果 S1P 1μM和10 μM处理组细胞增殖明显增加,S1P1受体激动剂也明显促进人胚胎肺纤维细胞增殖,Western blot结果显示S1P和SEW2871处理过的细胞磷酸化ERK和Akt表达增加,ERK及PI3K/Akt抑制剂可有效抑制S1P引起的细胞增殖作用.结论 S1P与S1P1受体结合并通过ERK1/2 和PI3K/Akt通路引起人胚胎肺纤维细胞增殖;S1P通过引起纤维细胞的增殖反应可能参与肺损伤的修复过程.     

1-磷酸鞘氨醇与支气管哮喘

1-磷酸鞘氨醇是一类生物活性鞘脂类代谢物,不仅可以作为第一信使与G蛋白耦联受体结合,也可以作为第二信使参与调节细胞的发育、增殖、重塑、生存和活化细胞等生物效应.近些年的研究证实,1-磷酸鞘氨醇及其信号通路对于支气管哮喘的发生、发展起到了非常重要的作用.这将或许为支气管哮喘的治疗提供一个新途径,本文主要就1-磷酸鞘氨醇与支气管哮喘的关系作一综述.     

1-磷酸鞘氨醇与支气管哮喘

1-磷酸鞘氨醇是一类生物活性鞘脂类代谢物,不仅可以作为第一信使与G蛋白耦联受体结合,也可以作为第二信使参与调节细胞的发育、增殖、重塑、生存和活化细胞等生物效应。近些年的研究证实,1-磷酸鞘氨醇及其信号通路对于支气管哮喘的发生、发展起到了非常重要的作用。这将或许为支气管哮喘的治疗提供一个新途径,本文主要就1-磷酸鞘氨醇与支气管哮喘的关系作一综述。     

Glycation of HDL Polymerizes Apolipoprotein M and Attenuates Its Capacity to Bind to Sphingosine 1-Phosphate

Aim: Recently, it has been established that most of the pleiotropic effects of high-density lipoprotein (HDL) are attributed to sphingosine 1-phosphate (S1P), which rides on HDL via apolipoprotein M (ApoM). In subjects with diabetes mellitus, both the pleiotropic effects of HDL and its role in reverse cholesterol transport are reported to be impaired. To elucidate the mechanisms underlying the impaired pleiotropic effects of HDL in subjects with diabetes, from the aspects of S1P and ApoM. Methods: The incubation of HDL in a high-glucose condition resulted in the dimerization of ApoM. Moreover, the treatment of HDL with methylglyoxal resulted in the modulation of the ApoM structure, as suggested by the results of western blot analysis, isoelectric focusing electrophoresis, and two-dimensional gel electrophoresis, which was reversed by treatment with anti-glycation reagents. Results: The glycation of HDL resulted in impaired binding of the glycated HDL to S1P, and the S1P on glycated HDL degraded faster. In the case of human subjects, on the other hand, although both the serum ApoM levels and the ApoM content in HDL were lower in subjects with diabetes, we did not observe the polymerization of ApoM. Conclusions: Modulation of the quantity and quality of ApoM might explain, at least in part, the impaired functions of HDL in subjects with diabetes mellitus. ApoM might be a useful target for laboratory testing and/or the treatment of diabetes mellitus.     

血清高敏C反应蛋白和1-磷酸鞘氨醇水平与冠心病严重程度的相关性研究

目的探讨血清高敏C反应蛋白(hs-CRP)和1-磷酸鞘氨醇(S1P)与冠心病的相关性。方法将122例行冠状动脉造影的患者分为对照组(59例)、冠心病组(63例),用Leaman积分系统对冠状动脉狭窄程度进行评分。采用多因素分析方法探讨冠心病及Leaman积分与血清hs-CRP、血浆中S1P、HDL相关S1P和non-HDL相关S1P含量因素的相关性。结果 (1)冠心病组hs-CRP水平明显高于对照组[(7.10±3.37)mg/L比(1.91±2.12)mg/L,P=0.014];冠心病组Leaman评分值明显高于对照组[(10.45±5.25)分比(3.25±2.35)分,P<0.01];(2)冠心病组血浆S1P水平高于对照组[(415.90±211.08)pmol/ml比(326.45±153.76)pmol/ml,P=0.046],冠心病组HDL-S1P水平与对照组比较,差异无统计学意义[(209.38±142.57)pmol/ml比(225.01±102.00)pmol/ml,P=0.072],冠心病组non-HDL-S1P水平明显高于对照组[(61.41±73.65)pmol/ml和(7.61±6.76)pmol/ml,P<0.01];(3)Logistic回归分析显示,吸烟、糖尿病、TG、LDL-C、non-HDL-S1P和hs-CRP与冠心病独立相关,而HDL-S1P与冠心病无相关性;(4)冠状动脉Leaman积分的多元逐步回归分析显示,non-HDL-S1P和hs-CRP与冠状动脉积分独立相关,其中以hs-CRP最为明显。结论 hs-CRP和nonHDL相关S1P为冠心病的独立危险因素,且与冠心病严重程度独立相关。     

Effect of S1P5 on proliferation and migration of human esophageal cancer cells

AIM:To investigate the sphingosine 1phosphate (S1P) receptor expression profile in human esophageal cancer cells and the effects of S1P5 on proliferation and migration of human esophageal cancer cells. METHODS: S1P receptor expression profile in human esophageal squamous cell carcinoma cell line Eca109 was detected by semiquantitative reverse trans cription polymerase chain reaction. Eca109 cells were stably transfected with S1P5EGFP or controlEGFP constructs. The relation between the responses of cell prol...     

HDL and its sphingosine-1-phosphate content in cardioprotection

Increasing evidence suggests that High-density lipoproteins (HDL) are a direct cardioprotective agent in the setting of acute myocardial ischemia/reperfusion injury, and that this cardioprotection occurs independently of their atheroprotective effect. Studies on the involved mechanisms have revealed that the biologically active HDL-compound sphingosine-1-phosphate (S1P) is responsible for the beneficial effect of HDL on the myocardium. There appears to be an intricate interplay between known preconditioning agents and components of the S1P synthesis machinery in the heart, which makes S1P signalling an attractive downstream convergence point of preconditioning and cardioprotection at the level of its G protein-coupled receptors. While local S1P production has been known to protect the heart against ischemia/reperfusion injury and to mediate preconditioning, systemic S1P supply via HDL adds a novel aspect to the regulation of cardioprotection. Thus the S1P-content of HDL may serve both as a potential cardiovascular risk marker and a novel therapeutic target. Strategies for short-term “acute” HDL elevation as well as S1P analogues may prove beneficial not only in the high-risk patient but also in any patient at risk of myocardial ischemia.     

1-磷酸鞘氨醇受体1参与晚期糖基化终产物引起的血管平滑肌细胞增殖和迁移

目的观察1-磷酸鞘氨醇受体1(S1PR1)在晚期糖基化终产物(AGE)引起的血管平滑肌细胞增殖和迁移中的作用。方法培养人脐动脉平滑肌细胞(HUASMC),葡萄糖与牛血清白蛋白(BSA)孵育法获得AGE-BSA,分为对照组、BSA组和AGE-BSA组,采用CCK-8实验检测平滑肌细胞增殖能力,采用细胞划痕和Transwell实验检测平滑肌细胞迁移能力,并进一步观察BSA和AGE-BSA在有或无S1PR1拮抗剂VPC23019/激动剂SEW2871预处理后的细胞增殖和迁移。结果与对照组比较,BSA和AGE-BSA均能诱导HUASMC增殖和迁移,AGE-BSA的作用比BSA更加显著(P0.05);S1PR1拮抗剂VPC23019可以明显抑制BSA和AGE-BSA诱导的HUASMC增殖和迁移;S1PR1激动剂SEW2871本身就可以促进HUASMC增殖和迁移,并且进一步促进BSA诱导的HUASMC增殖和迁移,而对AGE-BSA诱导的HUASMC增殖和迁移没有进一步的促进作用。结论血浆白蛋白本身对平滑肌细胞的增殖具有促进作用,糖基化修饰的白蛋白这一作用更加明显;S1PR1的激活参与了BSA和AGE-BSA促进平滑肌细胞增殖和迁移,AGE-BSA对S1PR1的激活作用更加显著。     

Implications of sphingosine kinase 1 expression level for the cellular sphingolipid rheostat: relevance as a marker for daunorubicin sensitivity of leukemia cells

We recently reported increased sphingosine kinase 1 (SPHK1) and decreased neutral sphingomyelinase 2 (NSMase2) gene expression in myelodysplastic syndromes and acute leukemia. This alteration is supposed to change the cellular sphingolipid metabolites; however, positive correlations were observed between daunorubicin (DA)-IC₅₀ and the SPHK1 message but not between DA-IC₅₀ and NSMase2 messages, when 16 different leukemia cell lines were used to analyze the relationship between gene expressions and chemosensitivity against DA. Using two cell lines with either the highest or lowest SPHK1 expression, cellular ceramides and sphingosine 1-phosphate (S1P) were quantified by liquid chromatography/mass spectrometry. Increased ceramide was observed in DA-sensitive, but not in DA-resistant cell lines treated with low doses of DA. Upon DA treatment, S1P decreased more in the sensitive cell lines than in resistant cell lines. A SPHK inhibitor recovered the DA sensitivity of DA-resistant cells. The modulation of SPHK1 gene expression by either overexpression or using siRNA affected the DA sensitivity of representative cell lines. Results clearly show that SPHK1 is both a good marker to predict the DA sensitivity of leukemia cells and a potential therapeutic target for leukemia with high SPHK1 expression, and suggest that the sphingolipid rheostat plays a significant role in DA-induced cytotoxicity.     

Platelet-derived sphingosine-1-phosphate and inflammation: from basic mechanisms to clinical implications

Beyond key functions in hemostasis and thrombosis, platelets are recognized as key players of inflammation, an underlying feature of a variety of diseases. In this regard, platelets act as a circulating source of several pro- and anti-inflammatory molecules, which are secreted from their intracellular stores upon activation. Among them, mounting evidence highlights a crucial role of sphingosine-1-phosphate (S1P), a multifunctional sphingoid mediator. S1P-induced pleiotropic effects include those crucial in inflammatory processes, such as the maintenance of the endothelial barrier integrity, and leukocyte activation and recruitment at the injured site. This review outlines the peculiar features and molecular mechanisms that allow platelets for acting as a unique factory that produces and stores S1P in large quantities. A particular emphasis is placed on the autocrine and paracrine roles of S1P derived from the “inflamed” platelets, highlighting the role of its cross-talk with endothelial and blood cells involved in inflammation, and the mechanisms of its contribution to the development and progression of inflammatory diseases. Finally, potential clinical implications of platelet-derived S1P as diagnostic tool of inflammatory severity, and as therapeutic target in inflammation are discussed.