BACKGROUND Little is known about whether mitochondria 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM). METHODS In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs). RESULTS Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (β 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (Pinteration < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33-1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function. CONCLUSION Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.

中文翻译：

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2型糖尿病患者的线粒体8-羟基-2'-脱氧鸟苷和冠状动脉疾病。

背景技术关于线粒体DNA（mtDNA）氧化损伤的生物标志物线粒体8-羟基-2'-脱氧鸟苷（8-OHdG）是否有助于糖尿病患者冠状动脉疾病（CAD）的发展还知之甚少。在这里，我们探讨了2型糖尿病（T2DM）患者中白细胞mtDNA 8-OHdG与阻塞性CAD，冠状动脉狭窄程度，心血管生物标志物和冠状动脉血运重建后1年不良结局的关系。方法横断面评估总共1920例因心绞痛或心绞痛等效症状而接受冠状动脉造影的T2DM患者，阻塞性CAD的存在，狭窄≥50％的患病血管数量以及改良的Gensini评分；通过定量PCR定量mtDNA 8-OHdG的水平。然后，在1920名进一步接受冠状动脉血运重建的糖尿病患者中，有701名完成了为期1年的前瞻性随访，以记录重大的不良心血管和脑事件（MACCE）。还进行了体外实验，以观察mtDNA氧化损伤在高葡萄糖培养的人脐静脉内皮细胞（HUVEC）中的作用。结果从横截面来看，更大的mtDNA 8-OHdG与阻塞性CAD的几率增加（比值比[OR] 1.38，95％CI置信区间1.24-1.52），冠状动脉狭窄程度更高（患病血管数：OR 1.29， 95％CI 1.19-1.41；修正的Gensini得分：校正混杂因素后，OR值为1.28，95％CI为1.18-1.39，C反应蛋白水平较高（β0.18，95％CI 0.06-0.31）。使用倾向得分匹配的敏感性分析得出了相似的结果。按吸烟状况分层显示，在当前吸烟者中，mtDNA 8-OHdG与阻塞性CAD之间的关联最为明显（Pinteration <0.01）。预测血管重建后1年MACCE的mtDNA 8-OHdG的每1-SD增加的调整风险比为1.59（95％CI 1.33-1.90）。在HUVEC中，暴露于抗霉素A（mtDNA氧化损伤的诱导剂）会导致线粒体和内皮功能标记物发生不利变化。结论白细胞中较高的mtDNA 8-OHdG可能是T2DM患者CAD的独立危险因素。90）用于预测血运重建后的1年MACCE。在HUVEC中，暴露于抗霉素A（mtDNA氧化损伤的诱导剂）会导致线粒体和内皮功能标记物发生不利变化。结论白细胞中较高的mtDNA 8-OHdG可能是T2DM患者CAD的独立危险因素。90）用于预测血运重建后的1年MACCE。在HUVEC中，暴露于抗霉素A（mtDNA氧化损伤的诱导剂）会导致线粒体和内皮功能标记物发生不利变化。结论白细胞中较高的mtDNA 8-OHdG可能是T2DM患者CAD的独立危险因素。