Data_Sheet_1_Relationship Between Plasma Osteopontin and Arginine Pathway Metabolites in Patients With Overt Coronary Artery Disease.docx

IntroductionOsteopontin (OPN) is involved in ectopic calcification. Its circulating form is upregulated in coronary artery disease (CAD) patients. Circulating OPN levels positively correlate with oxidative stress, one of the major triggers of endothelial dysfunction. Endothelial dysfunction is, in turn, associated with reduced nitric oxide (NO) bioavailability due to the impaired arginine pathway. The aim of this study was to better understand the correlations between OPN, oxidative stress markers, and the arginine pathway metabolites.
Methods and ResultsELISA and mass spectrometry techniques have been used to evaluate circulating OPN and arginine pathway/oxidative stress metabolites, respectively, in twenty-five control subjects and thirty-three patients with overt atherosclerosis. OPN positively correlates with 2,3-dinor-8isoPGF2a levels (p = 0.02), ornithine (p = 0.01), ADMA (p = 0.001), SDMA (p = 0.03), and citrulline (p = 0.008) levels only in CAD patients. In addition, citrulline positively correlated with ADMA (p = 0.02) levels, possibly as result of other sources of citrulline biosynthetic pathways.
ConclusionThe association between OPN and impaired arginine/NO pathway could play a role in the inhibition of endothelial NO synthase (eNOS) and/or in the arginase activation in the context of CAD patients. However, further studies are needed to verify the cause-effect relationship between OPN, oxidative stress, and arginine/NO pathway dysregulation.

引言：骨桥蛋白（Osteopontin, OPN）参与异位钙化进程，其循环形式在冠状动脉疾病（coronary artery disease, CAD）患者体内呈上调表达。循环OPN水平与氧化应激呈正相关，而氧化应激是诱发内皮功能障碍的主要触发因素之一。内皮功能障碍又可因精氨酸通路受损，导致一氧化氮（nitric oxide, NO）生物利用度降低而发生。本研究旨在深入阐明OPN、氧化应激标志物与精氨酸通路代谢物之间的关联。

材料与结果：本研究采用酶联免疫吸附试验（ELISA）与质谱技术，分别检测25名对照受试者与33例确诊动脉粥样硬化患者的循环OPN水平及精氨酸通路/氧化应激代谢物水平。结果显示，OPN仅在CAD患者中与2,3-二去甲-8-异前列腺素F2α（2,3-dinor-8isoPGF2α）、鸟氨酸、不对称二甲基精氨酸（Asymmetric dimethylarginine, ADMA）、对称二甲基精氨酸（Symmetric dimethylarginine, SDMA）及瓜氨酸水平呈正相关，对应p值分别为0.02、0.01、0.001、0.03及0.008。此外，瓜氨酸与不对称二甲基精氨酸（ADMA）水平呈正相关（p=0.02），这一现象可能与瓜氨酸生物合成通路的其他来源有关。

结论：OPN与受损的精氨酸/NO通路之间的关联，可能在CAD患者体内参与抑制内皮型一氧化氮合酶（endothelial nitric oxide synthase, eNOS）活性及/或激活精氨酸酶的过程中发挥作用。不过，仍需开展进一步研究以验证OPN、氧化应激与精氨酸/NO通路失调之间的因果关系。