HDL-Associated S1P as an Indicator of Relative Risk for Cardiovascular Disease

描述(申请人提供)：溶鞘糖脂，1-磷酸鞘氨醇(S1P)与脂蛋白，主要是高密度脂蛋白(高密度脂蛋白)一起携带在血液中。新的证据表明，高密度脂蛋白对心血管的许多影响可能与其S1P类物质有关。我们已经评估了人类血清中含有高密度脂蛋白的部分中S1P和相关鞘脂的水平如何与缺血性心脏病(IHD)的发生相关。为此，我们在哥本哈根城市心脏研究(CCHS)的204名受试者中，用液相色谱质谱联用法测量了含有部分高密度脂蛋白(去除低密度脂蛋白和极低密度脂蛋白)的高密度脂蛋白中的S1P水平。研究组包括高血清高密度脂蛋白胆固醇(HDLc)者(女性：E73.5 mg/dL；男性：E61.9 mg/dL)并确诊为IHD；高HDLc且无IHD者；低HDLc者(女性：D38.7 mg/dL；男性：D34.1 mg/dL)及IHD者，以及低HDLc且无IHD者。结果表明，血清中含高密度脂蛋白部分的S1P水平与IHD的发生呈高度显著的负相关。此外，在含高密度脂蛋白的血清部分中，还观察到另外两种鞘糖脂，二氢S1P和C24：1-神经酰胺与IHD有类似的相反关系。这些发现表明，高密度脂蛋白中鞘脂含量的组成差异可能对破译高密度脂蛋白在IHD中可能的保护作用具有重要意义。为了扩展我们的初步发现，我们将从CCHS血清样本中检测HDL中的S1P水平，以确定HDLS1P水平在评估IHD相对风险方面的预后价值。鉴于我们之前的研究不排除与另一种血浆S1P携带者白蛋白相关的S1P可能也与IHD的发生相关，我们计划确定与白蛋白相关的S1P水平是否与IHD的发生负相关。为了获得机制上的见解，我们打算在一个小鼠模型中测量低脂蛋白相关S1P水平对动脉粥样硬化过程的影响。此外，我们将测试假设，即含有降低水平的S1P的HDL在促进心脏保护信号的潜力方面是功能失调的。为了实现这一点，我们将评估来自CCHS受试者的高密度脂蛋白在特定水平的S1P促进内皮屏障活性和激活MAPK和Akt信号通路的能力。与公共健康相关：虽然有证据表明血液中高密度脂蛋白水平对心脏有保护作用，但也有一些高密度脂蛋白水平非常高的人患有心脏病，这表明高密度脂蛋白颗粒中可能存在质的差异，这使得它们在保护心脏方面的功能不同。我们发现，高密度脂蛋白水平高且有心脏病临床证据的人的鞘氨醇-1-磷酸(S1P)水平较低，这是一种通常由高密度脂蛋白携带的脂质，已被证明对心血管系统有许多有益的影响。在这项应用中，将进行实验，以检验高密度脂蛋白相关的S1P水平与心血管疾病风险负相关的假设，并确定S1P水平低于正常水平的高密度脂蛋白颗粒是否在心脏保护相关活动方面功能障碍。

DESCRIPTION (provided by applicant): The lysosphingolipid, sphingosine 1-phosphate (S1P) is carried in the blood in association with lipoproteins, predominantly high density lipoproteins (HDL). Emerging evidence indicates that many of the cardiovascular effects of HDL may be attributable to its S1P cargo. We have evaluated how levels of S1P and related sphingolipids in the HDL-containing fraction of human serum correlate with occurrence of ischemic heart disease (IHD). To accomplish this we used liquid chromatography-mass spectrometry to measure S1P levels in an HDL containing fraction of serum (depleted of LDL and VLDL) from 204 subjects in the Copenhagen City Heart Study (CCHS). The study group consisted of individuals having high serum HDL cholesterol (HDL-C) (females:e 73.5 mg/dL; males:e 61.9mg/dL) and verified IHD; subjects with high HDL-C and no IHD; individuals with low HDL-C (females:d 38.7 mg/dL; males:d 34.1 mg/dL) and IHD, and subjects with low HDL-C and no IHD. The results show a highly significant inverse relationship between the level of S1P in the HDL-containing fraction of serum and the occurrence of IHD. Furthermore, a similar inverse relationship with IHD was also observed for two other sphingolipids, dihydro-S1P and C24:1-ceramide, in the HDL- containing fraction of serum. These findings indicate that compositional differences in sphingolipid content of HDL might be important in deciphering the putative protective role of HDL in IHD. To extend on our preliminary findings we will measure S1P levels in HDLs from CCHS serum samples to determine the prognostic value of HDL-S1P levels in assessing the relative risk for IHD. Given that our previous studies do not preclude that S1P associated with another plasma S1P carrier, albumin, might also correlate with occurrence of IHD, we plan to determine whether S1P levels associated with albumin inversely correlate with occurrence of IHD. To gain mechanistic insights, we intend to measure the impact of low serum levels of lipoprotein-associated S1P on the process of atherosclerosis in a mouse model. In addition, we will test the hypothesis that HDLs containing reduced levels of S1P are dysfunctional with respect to their potential to promote cardioprotective signaling. To accomplish this we will evaluate the ability of HDLs from CCHS subjects with defined levels of S1P to promote endothelial barrier activity and activate the Map kinase and Akt signaling pathways. PUBLIC HEALTH RELEVANCE: While evidence indicates that high blood levels of HDL are cardioprotective, there are individuals with very high levels of HDL that have heart disease suggesting that qualitative differences might exist in HDL particles which make them functionally different with respect to cardioprotection. We have discovered that individuals with high levels of HDL and clinical evidence of heart disease have low levels of sphingosine-1-phosphate (S1P), a lipid normally carried on HDL that has been shown to have a number of beneficial effects on the cardiovascular system. In this application, experimentation will be performed to test the hypothesis that HDL-associated S1P levels inversely correlate with cardiovascular disease risk and to determine whether HDL particles with lower than normal levels of S1P are dysfunctional with respect to cardioprotective-related activities.