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首页> 外文期刊>EBioMedicine >Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease
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Elevated Markers of Death Receptor-Activated Apoptosis are Associated with Increased Risk for Development of Diabetes and Cardiovascular Disease

机译：死亡受体激活的细胞凋亡标志物升高与糖尿病和心血管疾病发展的风险增加相关

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Background An increased rate of cell death by apoptosis has been implicated in both diabetes and atherosclerosis. Apoptosis can be induced through activation of the death receptors TNF receptor 1 (TNFR-1), TRAIL receptor 2 (TRAILR-2) and Fas. Soluble forms of these receptors are found in plasma. The objective of this study was to determine if soluble death receptors are markers of receptor-activated apoptosis and predict risk for development of diabetes and cardiovascular events. Methods Fas ligand was used to induce apoptosis in peripheral blood mononuclear cells and INS-1 pancreatic β-cells and release of TNFR-1, TRAILR-2 and Fas measured by ELISA. Proximity Extension Assay was used to analyze plasma levels of TNFR-1, TRAILR-2 and Fas in baseline samples of 4742 subjects in the Malm? Diet and Cancer Study and related to development of diabetes and cardiovascular events during 19.2 years of follow-up. Results Activation of apoptosis by Fas ligand was associated with release of soluble Fas, TNFR-1 and TRAILR-2 in both cell types. Circulating levels of all three receptors were higher in subjects with diabetes and correlated with markers of impaired glucose metabolism in non-diabetic subjects. Among the latter, those in the highest tertile of soluble Fas, TNFR-1 and TRAILR-2 had increased risk for development of diabetes and cardiovascular events. These associations became weaker when adjusting for cardiovascular risk factors in Cox regression models, but remained significant for TRAILR-2 with incident diabetes, cardiovascular mortality, myocardial infarction and ischemic stroke, and for TNFR-1 with myocardial infarction. Conclusion The present study demonstrates an association between several cardiovascular risk factors and elevated levels of circulating markers of apoptotic cell death. It also shows that subjects with high levels of these biomarkers have increased risk of diabetes and CVD. This implies that soluble death receptors are markers of β-cell and vascular injury and potentially could be used as surrogate markers of therapeutic efficiency in risk factor interventions.
机译：背景技术糖尿病和动脉粥样硬化均与细胞凋亡导致的细胞死亡增加有关。凋亡可以通过激活死亡受体TNF受体1（TNFR-1），TRAIL受体2（TRAILR-2）和Fas来诱导。这些受体的可溶性形式存在于血浆中。这项研究的目的是确定可溶性死亡受体是否是受体激活的细胞凋亡的标志物，并预测糖尿病和心血管事件发生的风险。方法用Fas配体诱导外周血单个核细胞和INS-1胰腺β细胞凋亡，并用ELISA法检测TNFR-1，TRAILR-2和Fas的释放。邻近延伸分析用于分析马尔默地区4742名受试者的基线样本中的血浆TNFR-1，TRAILR-2和Fas水平。饮食和癌症研究以及与19.2年随访期间的糖尿病和心血管事件的发生有关。结果Fas配体激活细胞凋亡与两种细胞中可溶性Fas，TNFR-1和TRAILR-2的释放有关。糖尿病患者中所有三种受体的循环水平较高，并且与非糖尿病患者中糖代谢受损的标志物相关。在后者中，可溶性Fas，TNFR-1和TRAILR-2的最高三分位数的人罹患糖尿病和心血管事件的风险增加。当在Cox回归模型中调整心血管危险因素时，这些关联变得更弱，但对于TRAILR-2（合并糖尿病），心血管疾病死亡率，心肌梗塞和缺血性卒中，以及TNFR-1（合并心肌梗塞）仍然很重要。结论本研究证明了几种心血管危险因素与凋亡细胞死亡循环标志物水平升高之间的关联。这也表明，这些生物标志物含量高的受试者罹患糖尿病和CVD的风险增加。这意味着可溶性死亡受体是β细胞和血管损伤的标志物，并有可能在危险因素干预中用作治疗效率的替代标志物。

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