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

性状（由申请人提供）：溶血鞘脂、1-磷酸鞘氨醇（S1 P）与脂蛋白（主要是高密度脂蛋白（HDL））一起携带在血液中。新出现的证据表明，HDL的许多心血管效应可能归因于其S1 P货物。我们评估了人血清中含HDL部分中S1 P和相关鞘脂水平与缺血性心脏病（IHD）发生的相关性。为了实现这一点，我们使用液相色谱-质谱法来测量来自哥本哈根城市心脏研究（CCHS）中的204名受试者的血清中含有HDL的部分（LDL和VLDL耗尽）中的S1 P水平。研究组包括高血清HDL胆固醇（HDL-C）（女性：e 73.5 mg/dL;男性：e 61.9 mg/dL）和经证实的IHD受试者;高HDL-C但无IHD的受试者;低HDL-C（女性：d 38.7 mg/dL;男性：d 34.1 mg/dL）和IHD的受试者，以及低HDL-C但无IHD的受试者。结果表明，血清中含有HDL的部分中的S1 P水平与IHD的发生之间存在非常显著的负相关关系。此外，在含HDL的血清部分中，还观察到其他两种鞘脂（二氢-S1 P和C24：1-神经酰胺）与IHD的类似反比关系。这些发现表明，成分的差异，鞘脂含量的HDL可能是重要的破译假定的保护作用，HDL在IHD。为了扩展我们的初步研究结果，我们将测量CCHS血清样本中HDL的S1 P水平，以确定HDL-S1 P水平在评估IHD相对风险中的预后价值。鉴于我们以前的研究并不排除与另一种血浆S1 P载体白蛋白相关的S1 P也可能与IHD的发生相关，我们计划确定与白蛋白相关的S1 P水平是否与IHD的发生负相关。为了获得机制的见解，我们打算在小鼠模型中测量低血清水平的脂蛋白相关S1 P对动脉粥样硬化过程的影响。此外，我们将测试的假设，即HDL含有降低水平的S1 P是功能障碍方面的潜力，以促进心脏保护信号。为了实现这一点，我们将评估来自CCHS受试者的HDL的能力，其具有确定的S1 P水平，以促进内皮屏障活性并激活Map激酶和Akt信号通路。公共卫生相关性：虽然有证据表明高血液水平的HDL具有心脏保护作用，但有具有非常高水平的HDL的个体患有心脏病，这表明HDL颗粒中可能存在质的差异，这使得它们在心脏保护方面功能不同。我们发现，具有高水平HDL和心脏病临床证据的个体具有低水平的鞘氨醇-1-磷酸（S1 P），这是一种通常由HDL携带的脂质，已被证明对心血管系统具有许多有益的影响。在本申请中，将进行实验以检验HDL相关的S1 P水平与心血管疾病风险负相关的假设，并确定具有低于正常水平的S1 P的HDL颗粒是否在心脏保护相关活性方面功能障碍。

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.